Fumarate ester dosage forms

ABSTRACT

Described herein are pharmaceutical compositions comprising fumarate esters, methods for making the same, and methods for treating subjects in need thereof. In particular, oral controlled release pharmaceutical compositions comprising fumarate esters suspended in liquid matrices are described. One embodiment described herein is a pharmaceutical composition comprising fumarate esters suspended in a lipid or lipophilic liquid with enhanced bioavailability.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/129,887, filed Sep. 13, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/730,825, filed Oct. 12, 2017, which is acontinuation of U.S. patent application Ser. No. 15/386,175, filed Dec.21, 2016, which is a continuation of U.S. patent application Ser. No.15/248,506, filed Aug. 26, 2016, which claims priority to U.S.Provisional patent Application No. 62/300,941, filed on Feb. 29, 2016,and U.S. Provisional patent Application No. 62/356,872, filed on Jun.30, 2016; and is a continuation in part of U.S. patent application Ser.No. 14/840,072, now issued as U.S. Pat. No. 9,326,947, and claimspriority to International patent Application No. PCT/US2015/47636, bothfiled on Aug. 31, 2015; each of which is incorporated herein in itsentirety by express reference thereto.

TECHNICAL FIELD

Described herein are pharmaceutical compositions comprising fumarateesters, methods for making the same, and methods for treating subjectsin need thereof. In particular, oral controlled release pharmaceuticalcompositions comprising fumarate esters suspended in liquid matrices aredescribed. One embodiment described herein is a pharmaceuticalcomposition comprising fumarate esters suspended in a lipid orlipophilic liquid with enhanced bioavailability.

BACKGROUND

Fumaric acid esters (FAE; fumarate esters, e.g., alkyl or dialkylfumarate esters such as dimethyl fumarate or monomethyl fumarate) arepharmacologically active substances used for treatinghyperproliferative, inflammatory, or autoimmune disorders. They werefirst used to treat psoriasis and were licensed for this indication inGermany in 1995 as Fumaderm® (Biogen Idec, Inc., Cambridge, Mass., USA).Fumaderm® produces various undesirable side effects, including flushing,headaches, dizziness, eructation, nausea, vomiting, abdominal andintestinal cramps, and diarrhea. High concentrations of the drugreleased in the stomach are believed to be responsible for such sideeffects.

After oral intake, the main component of Fumaderm®, dimethyl fumarate(DMF), is hydrolysed by esterases to monomethyl fumarate (MMF), thebioactive metabolite. After absorption in the small intestine, MMF isbelieved to interact with immunocytes in the bloodstream. The primaryplasma metabolites of DMF are monomethyl fumarate, fumaric acid, citricacid, and glucose. Monomethyl fumarate is further metabolized in thetricarboxylic acid cycle to carbon dioxide and water.

An oral formulation of DMF was developed and approved for the treatmentof multiple sclerosis. This formulation, TECFIDERA® (Biogen Idec, Inc.),is available as hard gelatin delayed-release capsules containing 120 mgor 240 mg of granulated dimethyl fumarate enterically coatedminitablets. See International Patent Application Publication No. WO2013/119677 and U.S. Pat. No. 6,509,376. TECFIDERA® was intended toreduce the undesirable side effects by preventing release of DMF in thestomach.

The enterically coated DMF granules in TECFIDERA®, however, lackuniformity in shape and size, and the enteric coating may not be evenlydistributed over the minitablets. This lack of homogeneity can diminishthe enteric properties and affect the acid-resistance, dissolution, andrelease rates. In addition, the integrity of the acid-resistant coatingfails when the coating cracks or flakes off. This leads to DMF releasein the stomach and can cause flushing and the negative gastrointestinalside effects.

A subject's stomach content also affects delivery of DMF fromTECFIDERA®. A meal was shown to decrease C_(max) by 40% and delayT_(max) from 2.0 hours to 5.5 hours; the AUC was unaffected. See WO2006/037342. A reduction in the incidence of flushing by approximately25% in the postprandial state was also observed. See TECFIDERA®Prescribing Information 03/2013 (Biogen Idec Inc.).

DMF sublimes at relatively low temperatures. About 15-20% of the DMFactive ingredient is lost owing to sublimation during thewet-granulation processing used to manufacture TECFIDERA®. See WO2013/076216. Sublimation also causes loss of DMF during storage andunused TECFIDERA® capsules must be discarded 90 days after a bottle ofthe capsules is opened.

Accordingly, it is desirable to develop oral controlled releaseformulations of fumarate esters that: (1) provide enchancedbioavailability of the fumarate esters as compared to TECFIDERA® orother solid dosage forms comprising granulated forms or minitablets; (2)prevent flushing and the undesirable GI side effects associated withoral administration of fumarate esters; (3) reduce or eliminate fumarateester sublimation during manufacturing and storage; (4) increase thelong-term stability of the pharmaceutical composition; and (5) provide avariety of different release profiles, dose strengths, dosage forms, anddosing regimens.

SUMMARY

One embodiment described herein is an oral pharmaceutical compositioncomprising a liquid suspension of solid particles of one or morefumarate esters comprising dimethyl fumarate, monomethyl fumarate, apro-drug of monomethyl fumarate, or a combination thereof. In anotherembodiment, the oral pharmaceutical compositions have enhancedbioavailability and can be administered at lower doses of fumarate esterwith equivalent clinical efficacy.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising a liquid suspension of one or more fumarateesters comprising dimethyl fumarate, monomethyl fumarate, a pro-drugthereof, or a combination thereof. In one aspect, the liquid comprises aflowable, single-phase liquid. In another aspect, the liquid comprises anon-aqueous liquid. In another aspect, the liquid comprises a lipid orlipophilic liquid vehicle. In another aspect, the composition comprisesabout 80 mg to about 230 mg of the fumarate ester. In another aspect,the composition comprises about 90 mg to about 115 mg of the fumarateester. In another aspect, the composition comprises about 180 mg toabout 220 mg of the fumarate ester. In another aspect, the compositioncomprises about 180 mg to about 200 mg of the fumarate ester. In anotheraspect, the liquid comprises a lipid vehicle, one or more solubilityenhancing agents, and a neutralizing agent. In another aspect, the oneor more solubility enhancing agents comprise polyvinylpyrrolidone,polyoxyl 40 hydrogenated castor oil, or a combination thereof. Inanother aspect, the liquid comprises mono- and di-glycerides,polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, and lacticacid. In another aspect, the weight ratio of the fumarate ester tonon-aqueous liquid is about 1:1 to about 1:8. In another aspect, theweight ratio of the fumarate ester to non-aqueous liquid is about 1:2.In another aspect, the fumarate ester comprises about 10% to about 50%of the composition by weight. In another aspect, the fumarate estercomprises about 20% to about 40% of the composition by weight. Inanother aspect, the fumarate ester comprises about 30% to about 40% ofthe composition by weight. In another aspect, the fumarate estercomprises about 35% of the composition by weight. In another aspect, theliquid comprises about 50% to about 85% of the composition by weight. Inanother aspect, the liquid comprises about 60% to about 70% of thecomposition by weight. In another aspect, the liquid comprises about 60%of the composition by weight. In another aspect, lactic acid comprisesabout 5% of the composition by weight. In another aspect, thecomposition comprises: about 30% to about 40% by weight of the one ormore fumarate esters; about 55% to about 65% by weight of the liquid;and about 5% by weight of lactic acid. In another aspect, thecomposition comprises about 90 mg to about 220 mg of one or morefumarate esters. In another aspect, the composition comprises about 95mg of one or more fumarate esters. In another aspect, the compositioncomprises about 100 mg of one or more fumarate esters. In anotheraspect, the composition comprises about 200 mg to about 220 mg of one ormore fumarate esters. In another aspect, the composition comprises about200 mg of one or more fumarate esters. In another aspect, thecomposition is encapsulated in a capsule. In another aspect, thecomposition is encapsulated in a soft capsule. In another aspect, thecomposition is encapsulated in an enterically coated soft capsule. Inanother aspect, the enteric coating comprises an acrylic polymer orcopolymer. In another aspect, the composition is encapsulated in anenterically coated soft capsule shell comprising a subcoating. Inanother aspect, the subcoating comprises hydroxypropylmethylcellulose.In another aspect, the composition is encapsulated in an entericallycoated soft capsule shell comprising a topcoating. In another aspect,the topcoating comprises polyvinyl alcohol. In another aspect, thefumarate ester is a prodrug to monomethyl fumarate. In another aspect,the fumarate ester is dimethyl fumarate. In another aspect, the fumarateester is monomethyl fumarate.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising: about 12% to about 40% by weight of one or morefumarate esters; about 50% to about 80% by weight of mono- anddi-glycerides; about 5% to about 15% by weight of polyoxyl 40hydrogenated castor oil; about 1% to about 5% by weight ofpolyvinylpyrrolidone; and about 1% to about 5% by weight lactic acid. Inanother aspect, the composition comprises: about 34% by weight one ormore fumarate esters; about 48% by weight mono- and di-glycerides; about10% by weight polyoxyl 40 hydrogenated castor oil; about 3% by weightpolyvinylpyrrolidone; and about 5% by weight lactic acid. In anotheraspect, the composition comprises about 80 mg to about 110 mg or about160 mg to about 230 mg of the fumarate ester. In another aspect, thecomposition comprises about 90 mg to about 100 mg of the fumarate ester.In another aspect, the composition comprises about 180 mg to about 220mg of the fumarate ester. In another aspect, the composition comprisesabout 190 mg to about 200 mg of the fumarate ester. In another aspect,the composition is encapsulated in a capsule shell. In another aspect,the composition is encapsulated in a capsule comprising one or moresubcoatings, one or more enteric coatings, and one or more top coatings.In another aspect, the fumarate ester is a pro-drug of monomethylfumarate. In another aspect, the fumarate ester is dimethyl fumarate. Inanother aspect, the fumarate ester is monomethyl fumarate.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising a liquid suspension of one or more fumarateesters that is bioequivalent to a 240 mg dose of TECFIDERA® (dimethylfumarate). In one aspect, the composition comprises about 190 mg toabout 220 mg of the fumarate ester. In another aspect, bioequivalence isachieved by simultaneously administering two dosage forms, eachcomprising about 90 mg to about 100 mg of the fumarate ester. In anotheraspect, the composition comprises about 190 mg to about 200 mg ofdimethyl fumarate, monomethyl fumarate, a pro-drug thereof, or acombination thereof. In another aspect, the composition comprises about190 mg to about 200 mg of dimethyl fumarate or monomethyl fumarate.

Another embodiment described herein is a method of treating or reducingthe symptoms of multiple sclerosis in a subject, the method comprisingcontacting peripheral blood mononuclear cells or monocytes of thesubject with monomethyl fumarate by administering in an oralpharmaceutical composition comprising one or more fumarate esters in aliquid vehicle. In another aspect, the composition comprises a liquidsuspension of solid particles of dimethyl fumarate, monomethyl fumarate,pro-drugs thereof, or combinations thereof. In another aspect, theliquid comprises a flowable, single-phase liquid. In another aspect, theliquid comprises a non-aqueous liquid. In another aspect, the liquidcomprises a lipid or lipophilic liquid vehicle. In another aspect, thecomposition comprises about 80 mg to about 115 mg or about 160 mg toabout 230 mg of the fumarate ester. In another aspect, the compositioncomprises about 95 mg to about 100 mg of the fumarate ester. In anotheraspect, the composition comprises about 180 mg to about 220 mg of thefumarate ester. In another aspect, the composition comprises about 190mg to about 200 mg of the fumarate ester. In another aspect, the liquidcomprises a lipid vehicle, one or more solubility enhancing agents, anda neutralizing agent. In another aspect, the one or more solubilityenhancing agents comprise polyvinylpyrrolidone, polyoxyl 40 hydrogenatedcastor oil, or a combination thereof. In another aspect, the liquidcomprises mono- and di-glycerides, polyvinylpyrrolidone, polyoxyl 40hydrogenated castor oil, and lactic acid. In another aspect, the weightratio of the fumarate ester to non-aqueous liquid is about 1:1 to about1:8. In another aspect, the composition comprises: about 30% to about40% by weight of the one or more fumarate esters; about 55% to about 65%by weight of the liquid; and about 5% by weight of lactic acid. Inanother aspect, the composition comprises: about 12% to about 40% byweight of the one or more fumarate esters; about 50% to about 80% byweight of mono- and di-glycerides; about 5% to about 15% by weight ofpolyoxyl 40 hydrogenated castor oil; about 1% to about 5% by weight ofpolyvinylpyrrolidone; and about 1% to about 5% by weight lactic acid. Inanother aspect, the administration comprises: (a) administering twodosage froms simultaneously comprising about 80 mg to about 115 mg offumarate ester twice per day (BID); (b) administering one dosage fromcomprising about 80 mg to about 115 mg of fumarate ester four times perday; or (c) administering one dosage from comprising about 160 to about230 mg of fumarate ester twice per day (BID). In another aspect, theadministration comprises a total daily dosage of about 160 mg to about440 mg of the fumarate ester. In another aspect, the administrationcomprises a total daily dosage of about 160 mg, about 180 mg, about 190mg, about 200 mg, about 220 mg, about 230 mg, about 360 mg, about 380mg, about 400 mg, or about 440 mg of the fumarate ester. In anotheraspect, the subject achieves a reduction of annualized relapse raterelative to baseline without substantially experiencing one or more offlushing, abdominal pain, diarrhea, or nausea. In another aspect, thesubject exhibits one or more pharmacokinetic parameters comprising: (a)a mean plasma monomethyl fumarate C_(max) ranging from about 1.87 mg/Lto about 2.41 mg/L; (b) mean plasma monomethyl fumarate AUC_(0→∞)ranging from about 1.99 h·mg/L to about 2.43 h·mg/L; or (c) a meanplasma monomethyl fumarate AUC_(overall) ranging from about 3.2 h·mg/Lto about 11.2 h·mg/L.

Another embodiment described herein is a method of treating multiplesclerosis or psoriasis comprising administering to a subject one or moredosage forms that cumulatively provide a daily dosage of a fumarateester from about 360 mg to about 440 mg fumarate ester.

Another embodiment described herein is a method of treating multiplesclerosis or psoriasis comprising administering to a subject one or moredosage forms that cumulatively provide a daily dosage of a fumarateester from about 160 mg to about 230 mg fumarate ester. In one aspect,the administration is twice per day. In another aspect, two dosage fromscomprising between about 80 mg to about 115 mg of fumarate ester aresimultaneously administered twice per day.

Another embodiment described herein is an oral pharmaceuticalcomposition for activating a nuclear factor (erythroid-derived 2)-like 2(Nrf2) pathway comprising a liquid suspension of one or more fumarateesters comprising dimethyl fumarate, monomethyl fumarate, a pro-drugthereof, or a combination thereof.

Another embodiment described herein is a method for activating a nuclearfactor (erythroid-derived 2)-like 2 (Nrf2) pathway comprisingadministering a liquid suspension of solid particles of one or morefumarate esters comprising dimethyl fumarate, monomethyl fumarate, apro-drug thereof, or a combination thereof.

Another embodiment described herein is a method of manufacturing an oralpharmaceutical composition comprising a liquid suspension of solidparticles of one or more fumarate esters comprising dimethyl fumarate,monomethyl fumarate, a pro-drug thereof, or a combination thereof.

Another embodiment described herein is a pharmaceutical compositioncomprising a liquid suspension of solid particles of one or morefumarate esters comprising dimethyl fumarate, monomethyl fumarate, apro-drug thereof, or a combination thereof, wherein the compositionexhibits an in vitro dissolution rate comprising about 50% dissolutionafter about 30 minutes to about 50 minutes at pH 6.8.

Another embodiment described herein is an oral pharmaceuticalcomposition providing a consistent fumarate ester release profile thatreduces side effects comprising a liquid suspension of solid particlesof one or more fumarate esters comprising dimethyl fumarate, monomethylfumarate, a pro-drug thereof, or a combination thereof.

Another embodiment described herein is a method for providing aconsistent fumarate ester release profile that reduces side effectscomprising administering a liquid suspension of solid particles of oneor more fumarate esters comprising dimethyl fumarate, monomethylfumarate, a pro-drug thereof, or a combination thereof to a subject inneed thereof.

Another embodiment described herein is a method for providing multiplesclerosis treatment to a subject in need thereof with increased subjectcompliance and optimal treatment outcome comprising administering aliquid suspension of solid particles of one or more fumarate esterscomprising dimethyl fumarate, monomethyl fumarate, a pro-drug thereof,or a combination thereof to a subject in need thereof.

Another embodiment described herein is a method for providing multiplesclerosis treatment to a subject in need thereof with improved treatmentoutcome compared to 240 mg TECFIDERA® (dimethyl fumarate) comprisingadministering a liquid suspension of solid particles of one or morefumarate esters comprising dimethyl fumarate, monomethyl fumarate, apro-drug thereof, or a combination thereof to a subject in need thereof.

Another embodiment described herein is a method for providing long-termmultiple sclerosis treatment with optimal treatment outcome to a subjectin need thereof comprising administering an oral pharmaceuticalcomposition comprising a liquid suspension of solid particles of one ormore fumarate esters comprising dimethyl fumarate, monomethyl fumarate,a pro-drug thereof, or a combination thereof to a subject in needthereof.

Another embodiment described herein is an oral pharmaceutical dosagefrom comprising liquid composition comprising: about 12% to about 40% byweight of one or more fumarate esters; about 50% to about 80% by weightof mono- and di-glycerides; about 5% to about 15% by weight of polyoxyl40 hydrogenated castor oil; about 1% to about 5% by weight ofpolyvinylpyrrolidone; and about 1% to about 5% by weight lactic acid;wherein the liquid composition is encapsulated in a capsule comprisingone or more subcoatings, one or more enteric coatings, one or more topcoatings, or a combination thereof. In one aspect, the fumarate estercomprises from about 80 mg to about 440 mg of dimethyl fumarate,monomethyl fumarate, a prodrug of monomethyl fumarate, or a combinationthereof. In another aspect, one or more dosage forms, administered in aregimen, is bioequivalent to 240 mg TECFIDERA® (dimethyl fumarate) andhas enhanced bioavailability.

Another embodiment described herein is a controlled releasepharmaceutical composition comprising one or more fumarate esterssuspended in a lipid or lipophilic matrix. The pharmaceuticalcomposition is encapsulated in a soft capsule. The oral soft capsulescomprising controlled release matrix compositions prevent release of thefumarate ester active ingredient in the gastric environment, but releasethe active ingredient in the intestine in a controlled manner. Thecompositions can be tailored to provide one or more release profiles,including immediate release, controlled release, delayed release, orextended release pharmacokinetics by the composition of the matrix fill.The formulations described herein comprise solid micronized particles offumarate esters suspended in a matrix. The controlled releasepharmaceutical composition comprising a matrix of fumarate estersreduce, ameliorate, or eliminate the undesirable gastrointestinal sideeffects observed with prior fumarate ester pharmaceuticals. Further, theformulations preclude or reduce sublimation of the fumarate ester duringmanufacturing and storage.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising a controlled release composition of one or morefumarate esters, including, but not limited to, dialkyl fumarates, alkylfumarates, dimethyl fumarate (DMF), monomethyl fumarate (MMF), orcombinations thereof. In one embodiment, the fumarate ester is DMF. Inone embodiment, the fumarate ester is MMF. In one embodiment, thepharmaceutical composition comprises a controlled release pharmaceuticalcomposition. In another embodiment, the pharmaceutical compositioncomprises a soft capsule shell encapsulating a matrix comprising one ormore fumarate esters. In one aspect, the matrix comprises a lipid orlipophilic vehicle, a neutralizing agent, and solid particles offumarate esters. In another aspect, the matrix comprises a lipid orlipophilic vehicle, a neutralizing agent, excipients, and solidparticles of a fumarate ester. In another aspect, the matrix comprises alipid or lipophilic vehicle, a neutralizing agent, surfactants, andsolid particles of a fumarate ester. In one aspect, the lipid orlipophilic vehicle comprises polyvinylpyrrolidones, mono- anddi-glycerides, and oils. In another aspect, the surfactant can comprisepolysorbate 80 or polyoxyl 40 hydrogenated castor oil. In anotheraspect, the solid particles of fumarate ester comprise milled ormicronized particles. In another aspect, the milled or micronizedparticles of one or more fumarate esters comprise mean particledistribution sizes of about 20 μm to about 300 μm, including allintegers within the specified range. In another aspect, the solidparticles of fumarate esters comprise mean particle distribution sizesof about 65 μm to about 260 μm, including all integers within thespecified range. In another aspect, the solid microparticles of fumarateesters have mean particle distribution sizes of less than 260 μm. Inanother aspect, the solid particles of fumarate esters have meanparticle distribution sizes of about 100 μm. In another aspect, theneutralizing agent comprises an organic acid, ester, or salt. In anotheraspect, the neutralizing agent comprises at least one of lactate,fumarate, caprylate, caprate, oleate, maleate, succinate, tartrate,citrate, glutamate, gluconate, or esters or salts thereof, orcombinations thereof. In another aspect, the matrix comprises a fumarateester, a mixture of mono- and di-glycerides, polyvinylpyrrolidone,polyoxyl 40 hydrogenated castor oil, and lactic acid.

In another embodiment, the pharmaceutical composition comprises a matrixfill comprising about 10% to about 64% by weight of one or more fumarateesters (PSD: d90≤100 μm); about 18% to about 70% by weight of a mixtureof mono- and di-glycerides; at least about 1% to about 10% by weightpolyvinylpyrrolidone; at least about 1% to about 10% by weight polyoxyl40 hydrogenated castor oil, and at least about 1% to about 5% by weightlactic acid.

In another embodiment, the pharmaceutical composition comprises a matrixfill comprising about 29% by weight of one or more fumarate esters (PSD:d90≤100 μm); about 54% by weight of a mixture of mono- anddi-glycerides; about 3% by weight polyvinylpyrrolidone; about 10% byweight polyoxyl 40 hydrogenated castor oil, and about 5% by weightlactic acid. In one aspect, the composition has controlled release,delayed release, or extended release properties. In one aspect, thecomposition comprises one or more FAEs in an amount of about 80 mg toabout 460 mg. In one aspect, the one or more FAEs comprise about 90 mgto about 110 mg. In one aspect, the composition comprises one or moreFAEs in an amount of about 170 mg to about 220 mg. In one aspect, thecomposition comprises one or more FAEs in an amount of about 340 mg toabout 440 mg. In one aspect, the composition comprises one or more FAEsin an amount of about 80 mg FAE, about 85 mg FAE, about 90 mg FAE, about95 mg FAE, about 100 mg FAE, about 105 mg FAE, about 110 mg FAE, about115 mg FAE, about 120 mg FAE, about 125 mg FAE, about 130 mg FAE, about135 mg FAE, about 140 mg FAE, about 145 mg FAE, about 150 mg FAE, about155 mg FAE, about 160 mg FAE, about 165 mg FAE, about 170 mg FAE, about175 mg FAE, about 180 mg FAE, about 185 mg FAE, about 190 mg FAE, about195 mg FAE, about 200 mg FAE, about 205 mg FAE, about 210 mg FAE, about215 mg FAE, about 220 mg FAE, about 225 mg FAE, about 230 mg FAE, about235 mg FAE, about 240 mg FAE, about 245 mg FAE, about 250 mg FAE, about255 mg FAE, about 260 mg FAE, about 265 mg FAE, about 270 mg FAE, about275 mg FAE, about 280 mg FAE, about 285 mg FAE, about 290 mg FAE, about295 mg FAE, about 300 mg FAE, about 305 mg FAE, about 310 mg FAE, about315 mg FAE, about 320 mg FAE, about 325 mg FAE, about 330 mg FAE, about335 mg FAE, about 340 mg FAE, about 345 mg FAE, about 350 mg FAE, about355 mg FAE, about 360 mg FAE, about 365 mg FAE, about 370 mg FAE, about375 mg FAE, about 380 mg FAE, about 385 mg FAE, about 390 mg FAE, about395 mg FAE, about 400 mg FAE, about 405 mg FAE, about 410 mg FAE, about415 mg FAE, about 420 mg FAE, about 425 mg FAE, about 430 mg FAE, about435 mg FAE, about 440 mg FAE, about 445 mg FAE, about 450 mg FAE, about455 mg FAE, about 460 mg FAE, about 465 mg FAE, about 470 mg FAE, about475 mg FAE, or about 480 mg FAE. In one aspect, the compositioncomprises one or more FAEs in an amount of about 0.5 mmol to about 4.0mmol FAE. In one aspect, the composition comprises one or more FAEs inan amount of about 0.7 mmol to about 3.7 mmol FAE. In another aspect,the composition comprises DMF, MMF, or a combination thereof. In anotheraspect, the matrix comprises DMF. In another aspect, the compositioncomprises MMF. In another aspect, the composition further comprises oneor more non-steroidal anti-inflammatory drugs (NSAIDS). In one aspect,the composition prevents sublimation of the fumarate ester duringmanufacturing. In another aspect, the composition prophylacticallyreduces the onset or ameliorates the symptoms of any flushing sideeffects. In another aspect, the composition reduces the onset orameliorates the severity of any gastrointestinal side effects. Inanother aspect, the composition is stable for at least 1 year atconditions comprising 25° C. and 60% relative humidity. In anotheraspect, the composition is stable for at least 2 years at conditionscomprising 25° C. and 60% relative humidity.

In one embodiment, the soft capsule comprises and enteric soft capsule.In one embodiment, the soft capsule shell comprises one or more enteric,acid-insoluble polymers, a film-forming polymer, a plasticizer, analkali-neutralizing agent, a solvent, and optionally, a coloring agent,a flavoring, or a pharmaceutical excipient.

In another embodiment, the enteric soft capsule shell comprises about20% to about 36% by weight of at least one film-forming polymer; about8% to about 20% by weight of at least one enteric, acid-insolublepolymer; about 15% to about 20% by weight of at least one plasticizer;about 1% to about 5% by weight of at least one alkali-neutralizingagent; about 20% to about 40% by weight of a solvent; optionally, about1% to about 5% by weight of an opacifying agent; and optionally, about0.05% to about 1% by weight of at least one coloring agent.

In another embodiment, the soft capsule shell comprises about 30% of atleast one film-forming polymer; about 10% by weight of at least oneenteric, acid-insoluble polymer; about 20% by weight of at least oneplasticizer; about 1% by weight of at least one alkali-neutralizingagent; about 37% by weight of a solvent; and optionally, about 1.5% byweight of an opacifying agent; and optionally, at least one coloringagent. In one aspect, the soft capsule shell comprises gelatin, acrylicmethacrylate copolymers, glycerol, triethyl citrate, ammonia, water, andtitanium dioxide.

Another embodiment described herein is a method for manufacturing anoral soft capsule shell encapsulating a matrix comprising a fumarateester, the method comprising: (i) providing a matrix fill compositioncomprising any of the composition described herein; (ii) providing asoft capsule shell composition comprising any of the compositiondescribed herein; (iii) casting the soft capsule shell into films usingheat-controlled drums or surfaces; and (iv) forming a soft capsule shellencapsulating the matrix fill composition using rotary die encapsulationtechnology. In one aspect, the soft capsule matrix comprises one or morefumarate esters produced by said method.

Another embodiment described herein is a method for manufacturing anoral soft capsule shell encapsulating a matrix comprising a fumarateester, the method comprising: (i) providing a matrix fill compositioncomprising: about 10% to about 64% by weight of one or more fumarateesters (PSD: d90≤100 μm); about 18% to about 70% by weight of a mixtureof mono- and di-glycerides; about 1% to about 10% by weightpolyvinylpyrrolidone; about 2% to about 12% by weight polyoxyl 40hydrogenated castor oil, and about 1% to about 5% by weight lactic acid;(ii) providing a soft capsule shell composition comprising: about 20% toabout 36% by weight of at least one film-forming polymer; about 8% toabout 20% by weight of at least one enteric, acid-insoluble polymer;about 15% to about 20% by weight of at least one plasticizer; about 1%to about 5% by weight of at least one alkali-neutralizing agent; about20% to about 40% by weight of a solvent; optionally, about 1% to about5% by weight of an opacifying agent; and optionally, about 0.05% toabout 1% by weight of at least one coloring agent; (iii) casting thesoft capsule shell into films using heat-controlled drums or surfaces;and (iv) forming a soft capsule shell encapsulating the matrix fillcomposition using rotary die encapsulation technology.

Another embodiment described herein is a soft capsule comprising a shellencapsulating a fumarate ester matrix, wherein the matrix comprises:about 10% to about 64% by weight of one or more fumarate esters (PSD:d90≤100 μm); about 18% to about 70% by weight of mono- anddi-glycerides; at least about 1% to about 7% by weight ofpolyvinylpyrrolidone; at least about 2% to about 10% by weight ofpolyoxyl 40 hydrogenated castor oil, and at least about 1% to about 5%by weight of lactic acid; and wherein the soft capsule shell comprises:about 20% to about 36% by weight of at least one film-forming polymer;about 8% to about 20% by weight of at least one enteric, acid-insolublepolymer; about 15% to about 20% by weight of at least one plasticizer;about 1% to about 5% by weight of at least one alkali-neutralizingagent; about 20% to about 40% by weight of a solvent; optionally, about1% to about 5% by weight of an opacifying agent; and optionally, about0.05% to about 1% by weight of at least one coloring agent.

Another embodiment described herein is a soft capsule comprising a shellencapsulating a fumarate ester matrix, wherein the matrix comprises:about 29% by weight of one or more fumarate esters (PSD: d90≤100 μm);about 54% by weight of a mixture of mono- and di-glycerides; about 3% byweight polyvinylpyrrolidone; about 10% by weight polyoxyl 40hydrogenated castor oil, and about 5% by weight lactic acid; and whereinthe soft capsule shell comprises: about 30% by weight of at least onefilm-forming polymer; about 10% by weight of at least one enteric,acid-insoluble polymer; about 20% by weight of at least one plasticizer;about 1% by weight of at least one alkali-neutralizing agent; about 37%by weight of a solvent; optionally, about 1.5% by weight of anopacifying agent; and optionally, at least one coloring agent. Inanother aspect, the composition comprises DMF, MMF, or a combinationthereof. In another aspect, the matrix comprises DMF. In another aspect,the composition comprises MMF. In one aspect, the soft capsulecomprising a fumarate ester is resistant to dissolution at about pH 1.2for at least about 2 hours. In another aspect, the soft capsulecomprising a fumarate ester begins dissolution at pH of about 6.8 withinabout 10 minutes. In one aspect, the soft capsule has immediate release,controlled release, delayed release, or extended release properties. Inanother aspect, the soft capsule comprising a fumarate ester reduces theonset or ameliorates the severity of any flushing or gastrointestinalside effects.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of multiple sclerosis or psoriasis,comprising administering to a subject in need thereof an oralpharmaceutical composition comprising a controlled release soft capsuleshell and matrix comprising a fumarate ester. In one aspect, thepharmaceutical composition comprises a controlled release soft capsulecomprising a formulation of fumarate ester. In one aspect, thepharmaceutical composition comprises a controlled release soft capsulecomprising a formulation of fumarate ester. In another aspect, thecomposition comprises DMF, MMF, or a combination thereof. In anotheraspect, the matrix comprises DMF. In another aspect, the compositioncomprises MMF.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising administering to a subject in needthereof an oral pharmaceutical composition comprising a controlledrelease formulation of a fumarate ester, wherein the subject achieves areduction of annualized relapse rate relative to baseline withoutsubstantially experiencing one or more of flushing, abdominal pain,diarrhea, and nausea. In one aspect, the pharmaceutical compositioncomprises any of the compositions described herein. In another aspect,the composition comprises DMF, MMF, or a combination thereof. In anotheraspect, the matrix comprises DMF. In another aspect, the compositioncomprises MMF.

Another embodiment described herein is an oral pharmaceuticalcomposition as described herein that is useful for treatingneurodegenerative disorders. In one aspect, the pharmaceuticalcomposition is useful for treating multiple sclerosis or psoriasis. Inone embodiment described herein, subjects that are administered the oralpharmaceutical composition as described herein exhibit a mean plasmamonomethyl fumarate T_(max) of from about 1.5 hours to about 3.5 hours.

Another embodiment described herein is an oral pharmaceuticalcomposition useful for treating, retarding the progression of, delayingthe onset of, prophylaxis of, amelioration of, or reducing the symptomsof general autoimmune or neurodegenerative disorders. In one aspect, thecomposition comprises DMF, MMF, or a combination thereof. In anotheraspect, the matrix comprises DMF. In another aspect, the compositioncomprises MMF.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of general autoimmune or neurodegenerativedisorders. In one aspect, the composition comprises DMF, MMF, or acombination thereof. In another aspect, the matrix comprises DMF. Inanother aspect, the composition comprises MMF.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising a controlled release composition comprising aformulation of a fumarate ester useful for treating, retarding theprogression of, delaying the onset of, prophylaxis of, amelioration of,or reducing the symptoms of general autoimmune or neurodegenerativedisorders, including but not limited to, acute dermatitis, adrenalleukodystrophy, AGE-induced genome damage, Alexander's disease, alopeciaareata (totalis and universalis), Alper's disease, Alzheimer's disease,amyotrophic lateral sclerosis, angina pectoris, arthritis, asthma,autoimmune diseases, balo concentric sclerosis, Behçet's syndrome,bullous pemphigoid, Canavan disease, cardiac insufficiency includingleft ventricular insufficiency, central nervous system vasculitis,Charcot-Marie-Tooth disease, childhood ataxia with central nervoussystem hypomyelination, chronic active (lupoid) hepatitis, chronicdermatitis, chronic idiopathic peripheral neuropathy, chronicobstructive pulmonary disease, contact dermatitis, Crohn's disease andcutaneous Crohn's disease, cutaneous lupus, cutaneous sarcoidosis,diabetic retinopathy, fibromyalgia, graft versus host disease, granulomaannulare, granulomas including annulare, Grave's disease, Hashimoto'sthyroiditis, hepatitis C viral infection, herpes simplex viralinfection, human immunodeficiency viral infection, Huntington's disease,inflammatory bowel disease, irritable bowel disorder, ischemia,juvenile-onset diabetes mellitus, Krabbe disease, lichen planus, maculardegeneration, mitochondrial encephalomyopathy, monomelic amyotrophy,multiple sclerosis (MS), myocardial infarction, necrobiosis lipoidica,neurodegeneration with brain iron accumulation, neurodermatitis,neuromyelitis optica, neuropathic pain, neurosarcoidosis, NF-κB mediateddiseases, optic neuritis, organ transplantation rejection,paraneoplastic syndromes, Parkinson's disease, Pelizaeus-Merzbacherdisease, pemphigus, pernicious anemia, primary lateral sclerosis,progressive supranuclear palsy, psoriasis, psoriatic arthritis, pyodermagangrenosum, radiation induced dermatitis, radicular pain,radiculopathic pain, reperfusion injury, retinopathic pigmentosa,rheumatoid arthritis (RA), sarcoidosis, sarcoidosis, Schilder's disease,sciatic pain, sciatica, Sjögren's syndrome, subacute necrotizingmyelopathy, such as polyarthritis, Susac's syndrome, systemic lupuserythematosus (SLE), tumors, transverse myelitis, ulcerative colitis, orZellweger syndrome. In one aspect, the composition comprises DMF, MMF,or a combination thereof. In another aspect, the matrix comprises DMF.In another aspect, the composition comprises MMF.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of general autoimmune or neurodegenerativedisorders, including but not limited to, acute dermatitis, adrenalleukodystrophy, AGE-induced genome damage, Alexander's disease, alopeciaareata (totalis and universalis), Alper's disease, Alzheimer's disease,amyotrophic lateral sclerosis, angina pectoris, arthritis, asthma,autoimmune diseases, balo concentric sclerosis, Behçet's syndrome,bullous pemphigoid, Canavan disease, cardiac insufficiency includingleft ventricular insufficiency, central nervous system vasculitis,Charcot-Marie-Tooth disease, childhood ataxia with central nervoussystem hypomyelination, chronic active (lupoid) hepatitis, chronicdermatitis, chronic idiopathic peripheral neuropathy, chronicobstructive pulmonary disease, contact dermatitis, Crohn's disease andcutaneous Crohn's disease, cutaneous lupus, cutaneous sarcoidosis,diabetic retinopathy, fibromyalgia, graft versus host disease, granulomaannulare, granulomas including annulare, Grave's disease, Hashimoto'sthyroiditis, hepatitis C viral infection, herpes simplex viralinfection, human immunodeficiency viral infection, Huntington's disease,inflammatory bowel disease, irritable bowel disorder, ischemia,juvenile-onset diabetes mellitus, Krabbe disease, lichen planus, maculardegeneration, mitochondrial encephalomyopathy, monomelic amyotrophy,multiple sclerosis (MS), myocardial infarction, necrobiosis lipoidica,neurodegeneration with brain iron accumulation, neurodermatitis,neuromyelitis optica, neuropathic pain, neurosarcoidosis, NF-κB mediateddiseases, optic neuritis, organ transplantation rejection,paraneoplastic syndromes, Parkinson's disease, Pelizaeus-Merzbacherdisease, pemphigus, pernicious anemia, primary lateral sclerosis,progressive supranuclear palsy, psoriasis, psoriatic arthritis, pyodermagangrenosum, radiation induced dermatitis, radicular pain,radiculopathic pain, reperfusion injury, retinopathic pigmentosa,rheumatoid arthritis (RA), sarcoidosis, sarcoidosis, Schilder's disease,sciatic pain, sciatica, Sjögren's syndrome, subacute necrotizingmyelopathy, such as polyarthritis, Susac's syndrome, systemic lupuserythematosus (SLE), tumors, transverse myelitis, ulcerative colitis, orZellweger syndrome comprising administering to a subject in need thereofan oral controlled release pharmaceutical composition comprising afumarate ester. In one embodiment described herein, the oralpharmaceutical composition comprises a soft capsule shell and matrixcomprising a fumarate ester. In one aspect, the pharmaceuticalcomposition comprises a controlled release soft capsule comprising aformulation of a fumarate ester. In another aspect, the pharmaceuticalcomposition is an immediate release, delayed release, controlledrelease, or extended release formulation of a fumarate ester. In anotheraspect, the composition comprises DMF, MMF, or a combination thereof. Inanother aspect, the matrix comprises DMF. In another aspect, thecomposition comprises MMF.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising a controlled release formulation of a fumarateester. In one aspect, the composition is provided in a dosage formcontaining about 85 mg to about 110 mg of one or more fumarate esters,wherein subjects administered the dose form four times daily exhibit oneor more pharmacokinetic parameters comprising: (a) a mean plasmamonomethyl fumarate C_(max) ranging from about 0.4 mg/L to about 2.41mg/L; or (b) a mean plasma monomethyl fumarate AUC_(overall) a rangingfrom about 3.2 h·mg/L to about 11.2 h·mg/L. In another aspect, thecomposition is provided in a dosage form containing about 120 mg toabout 180 mg of one or more fumarate esters, wherein subjectsadministered the dose form exhibit one or more pharmacokineticparameters comprising: (a) a mean plasma monomethyl fumarate C_(max)ranging from about 0.4 mg/L to about 2.41 mg/L; (b) a mean plasmamonomethyl fumarate AUC_(0→12 h) ranging from about 0.5 h·mg/L to about2.5 h·mg/L; or (c) a mean AUC_(→∞) ranging from about 0.5 h·mg/L toabout 2.6 h·mg/L. In another aspect, the composition is provided in adosage form containing a total amount of about 170 mg to about 220 mg ofone or more fumarate esters, wherein subjects administered the dose formtwice-daily exhibit one or more pharmacokinetic parameters comprising:(a) a mean plasma monomethyl fumarate C_(max) ranging from about 1.0mg/L to about 3.4 mg/L; (b) a mean plasma monomethyl fumarateAUC_(overall) ranging from about 4.81 h·mg/L to about 11.2 h·mg/L. Inanother aspect, the composition is provided in a dosage form containingabout 170 mg to about 220 mg of one or more fumarate esters, whereinsubjects administered the dose form exhibit one or more pharmacokineticparameters comprising: (a) a mean plasma monomethyl fumarate C_(max)ranging from about 1.0 mg/L to about 3.4 mg/L; (b) a mean plasmamonomethyl fumarate AUC_(0→12 h) ranging from about 1.0 h·mg/L to about5.5 h·mg/L; or (c) a mean AUC_(0→∞) ranging from about 1.0 h·mg/L toabout 5.6 h·mg/L. In another aspect, the fumarate ester formulation isencapsulated in a soft capsule. In another aspect, the compositioncomprises DMF, MMF, or a combination thereof. In another aspect, thematrix comprises DMF. In another aspect, the composition comprises MMF.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising total amount of about 85 mg to about 110 mg ofone or more fumarate esters, wherein subjects administered the capsuleexhibit one or more pharmacokinetic parameters comprising: (a) a meanplasma monomethyl fumarate T_(max) of from about 1.5 hours to about 3.5hours; (b) a mean plasma monomethyl fumarate C_(max) ranging from about0.4 mg/L to about 2.41 mg/L; (c) a mean plasma monomethyl fumarateAUC_(0→12 h) ranging from about 0.5 h·mg/L to about 2.5 h·mg/L; or (d) amean AUC_(0→∞) ranging from about 0.5 h·mg/L to about 2.6 h·mg/L. Inanother aspect, the composition comprises about 170 mg to about 220 mgof one or more fumarate esters, wherein subjects administered thecapsule exhibit one or more pharmacokinetic parameters comprising: (a) amean plasma monomethyl fumarate T_(max) of from about 1.5 hours to about3.5 hours; (b) a mean plasma monomethyl fumarate C_(max) ranging fromabout 1.0 mg/L to about 3.4 mg/L; (c) a mean plasma monomethyl fumarateAUC_(0-12 h) ranging from about 1.0 h·mg/L to about 5.5 h·mg/L; or (d) amean AUC_(0→∞) ranging from about 1.0 h·mg/L to about 5.6 h·mg/L. In oneaspect, the composition comprises DMF, MMF, or a combination thereof. Inanother aspect, the matrix comprises DMF. In another aspect, thecomposition comprises MMF.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising orally administering to a subject inneed thereof a therapeutically effective amount of one or more fumarateesters comprising any of the compositions described herein and atherapeutically amount of one or more non-steroidal anti-inflammatorydrugs effective to reduce flushing. In one aspect, the one or morenon-steroidal anti-inflammatory drug is aspirin, ibuprofen, naproxene,diclofenac, ketoprofen, celecoxib, or a combination thereof.

Another embodiment described herein is a once or twice daily oralpharmaceutical composition comprising a delayed release, controlledrelease, or extended release formulation of a fumarate ester. In oneaspect, the composition is provided in one or more dosage formscontaining about 80 mg to about 460 mg of one or more fumarate esters,wherein subjects administered the dose form once daily exhibit one ormore pharmacokinetic parameters comprising: (a) a mean plasma monomethylfumarate C_(max) ranging from about 0.4 mg/L to about 5.2 mg/L; or (b) amean plasma monomethyl fumarate AUC_(0→∞) ranging from about 0.5 h·mg/Lto about 15.5 h·mg/L. In another aspect, the composition is provided inone or more dosage forms containing about 80 mg to about 460 mg of oneor more fumarate esters, wherein subjects administered the dose formonce daily exhibit one or more pharmacokinetic parameters comprising:(a) a mean plasma monomethyl fumarate C_(max) ranging from about 0.4mg/L to about 5.2 mg/L, (b) a mean plasma monomethyl fumarateAUC_(0→12 h) ranging from about 0.5 h·mg/L to about 13.5 h·mg/L, or (c)a mean AUC_(0→∞) ranging from about 0.5 h·mg/L to about 15.5 h·mg/L. Inanother aspect, the capsule contains a total amount of about 80 mg toabout 460 mg of one or more fumarate esters, wherein subjectsadministered the one or more capsules exhibit one or morepharmacokinetic parameters comprising: (a) a mean plasma monomethylfumarate T_(max) of from about 1.5 hours to about 10.5 hours; (b) a meanplasma monomethyl fumarate C_(max) ranging from about 0.4 mg/L to about5.2 mg/L; (c) a mean plasma monomethyl fumarate AUC_(0→12 h) rangingfrom about 0.5 h·mg/L to about 13.5 h·mg/L; or (d) a mean AUC_(0→∞)ranging from about 0.5 h·mg/L to about 15.5 h·mg/L.

Another embodiment described herein is a pharmaceutical composition asdescribed herein, for oral administration to a subject having multiplesclerosis containing one or more fumarate ester compounds, orpharmaceutically acceptable salts thereof that metabolize to monomethylfumarate, wherein said administering the composition provides one ormore of the following pharmacokinetic parameters: (a) a mean plasmamonomethyl fumarate T_(max) of from about 1.5 hours to about 3.5 hours;(b) a mean plasma monomethyl fumarate C_(max) ranging from about 0.4mg/L to about 3.4 mg/L; (c) a mean plasma monomethyl fumarateAUC_(overall) ranging from about 3.2 h·mg/L to about 11.2 h·mg/L; (d) amean plasma monomethyl fumarate AUC_(0→12 h) ranging from about 0.5h·mg/L to about 5.5 h·mg/L; or (e) a mean AUC_(0→∞) ranging from about0.5 h·mg/L to about 5.6 h·mg/L.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising administering to a subject in needthereof any one of the compositions of described herein, containing oneor more fumarate ester compounds, or pharmaceutically acceptable saltsthereof that metabolize to monomethyl fumarate, wherein saidadministering the composition provides one or more of the followingpharmacokinetic parameters: (a) a mean plasma monomethyl fumarateT_(max) of from about 1.5 hours to about 3.5 hours; (b) a mean plasmamonomethyl fumarate C_(max) ranging from about 0.4 mg/L to about 3.4mg/L; (c) a mean plasma monomethyl fumarate AUC_(overall) ranging fromabout 3.2 h·mg/L to about 11.2 h·mg/L; (d) a mean plasma monomethylfumarate AUC_(0→12 h) ranging from about 0.5 h·mg/L to about 5.5 h·mg/L;or (e) a mean AUC_(0→∞) ranging from about 0.5 h·mg/L to about 5.6h·mg/L.

Another embodiment described herein is a pharmaceutical composition asdescribed herein, for oral administration to a subject having multiplesclerosis containing one or more fumarate ester compounds, orpharmaceutically acceptable salts thereof that metabolize to monomethylfumarate, wherein said administering the composition provides one ormore of the following pharmacokinetic parameters: (a) a mean plasmamonomethyl fumarate T_(max) of from about 1.5 hours to about 10.5 hours;(b) a mean plasma monomethyl fumarate C_(max) ranging from about 0.4mg/L to about 5.2 mg/L; (c) a mean plasma monomethyl fumarateAUC_(0→12 h) ranging from about 0.5 h·mg/L to about 13.5 h·mg/L; or (d)a mean AUC_(0→∞) ranging from about 0.5 h·mg/L to about 15.5 h·mg/L.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising orally administering to a subject inneed thereof any one of the compositions described herein comprising oneor more fumarate ester compounds, or pharmaceutically acceptable saltsthereof that metabolize to monomethyl fumarate, wherein saidadministering the composition provides one or more of the followingpharmacokinetic parameters: (a) a mean plasma monomethyl fumarateT_(max) of from about 1.5 hours to about 10.5 hours; (b) a mean plasmamonomethyl fumarate C_(max) ranging from about 0.4 mg/L to about 5.2mg/L; (c) a mean plasma monomethyl fumarate AUC_(overall) ranging fromabout 0.5 h·mg/L to about 15.2 h·mg/L; (d) a mean plasma monomethylfumarate AUC_(0-12 h) ranging from about 0.5 h·mg/L to about 13.5h·mg/L; or (e) a mean AUC_(0→∞) ranging from about 0.5 h·mg/L to about15.5 h·mg/L. In one aspect, the composition comprises DMF, MMF, or acombination thereof. In another aspect, the matrix comprises DMF. Inanother aspect, the composition comprises MMF.

Another embodiment described herein is a pharmaceutical compositioncomprising any one of the pharmaceutical compositions described hereinfor oral administration to a subject having multiple sclerosis,comprising a therapeutically effective amount of one or more fumarateesters, wherein the administration is sufficient to achieve a reductionof about 0.224 annualized relapse rate relative to baseline in thesubject without substantially inducing one or more of flushing,abdominal pain, diarrhea, and nausea in the subject. In one aspect, thesubject experiences one or more of flushing, abdominal pain, diarrhea,and nausea at a rate of less than about 10%. In another aspect, thesubject is a child. In one aspect, the child is over 9 years of age.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of multiple sclerosis, the methodcomprising the oral administration of a therapeutically effective amountof one or more fumarate esters comprising any one of the pharmaceuticalcompositions described herein, to a subject with multiple sclerosis,wherein the administration is sufficient to achieve a reduction of about0.224 annualized relapse rate relative to baseline in the subjectwithout substantially inducing one or more of flushing, abdominal pain,diarrhea, and nausea in the subject. In one aspect, the subjectexperiences one or more of flushing, abdominal pain, diarrhea, andnausea at a rate of less than about 10%. In another aspect, the subjectis a child. In one aspect, the child is over 9 years of age.

Another embodiment described herein is a pharmaceutical compositioncomprising any one of the pharmaceutical compositions described hereinfor oral administration to a subject having multiple sclerosis,comprising a therapeutically effective amount of one or more fumarateesters, wherein the administration is sufficient to achieve a reductionof annualized relapse rate relative to baseline in the subject withoutsubstantially inducing one or more of flushing, abdominal pain,diarrhea, and nausea in the subject. In one aspect, the subjectexperiences one or more of flushing, abdominal pain, diarrhea, andnausea at a rate of less than about 10%. In another aspect, the subjectis a child. In one aspect, the child is over 9 years of age.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, the method comprising the oral administration ofa therapeutically effective amount of one or more fumarate esterscomprising any one of the pharmaceutical compositions described hereinto a subject in need thereof, wherein the subject achieves a reductionannualized relapse rate relative to baseline without substantiallyexperiencing one or more of flushing, abdominal pain, diarrhea, andnausea. In one aspect, the subject experiences one or more of flushing,abdominal pain, diarrhea, and nausea at an incidence rate of less thanabout 10%. In another aspect, the subject is a child. In one aspect, thechild is over 9 years of age.

Another embodiment described herein is a pharmaceutical compositioncomprising any one of the pharmaceutical compositions described herein,for oral administration to a subject having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis, comprising a therapeutically effective amount of one or morefumarate esters, wherein the administration is sufficient to achieve areduction of annualized relapse rate relative to baseline in the subjectwithout substantially inducing one or more of flushing, abdominal pain,diarrhea, and nausea in the subject; and wherein the administration doesnot require titration of the pharmaceutical composition. In one aspect,the subject experiences one or more of flushing, abdominal pain,diarrhea, and nausea at an incidence rate of less than about 10%. Inanother aspect, the subject is a child. In one aspect, the child is over9 years of age.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis, the method comprising the oral administration of atherapeutically effective amount of one or more fumarate esterscomprising any one of the pharmaceutical compositions described herein,to a subject in need thereof, wherein the administration is sufficientto achieve a reduction of annualized relapse rate relative to baselinein the subject without substantially inducing one or more of flushing,abdominal pain, diarrhea, and nausea in the subject; and wherein theadministration does not require titration of the pharmaceuticalcomposition.

Another embodiment described herein is a pharmaceutical compositioncomprising any of the pharmaceutical compositions described herein fororal administration to a subject having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis, comprising a therapeutically effective amount of one or morefumarate esters, wherein the administration is sufficient to achieve areduction of about 0.224 annualized relapse rate relative to baseline inthe subject without substantially inducing one or more of flushing,abdominal pain, diarrhea, and nausea in the subject and wherein theadministration does not require titration of the pharmaceuticalcomposition. In one aspect, the subject experiences one or more offlushing, abdominal pain, diarrhea, and nausea at a rate of less thanabout 10%. In another aspect, the subject is a child. In one aspect, thechild is over 9 years of age.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis, the method comprising the oral administration of atherapeutically effective amount of one or more fumarate esterscomprising any of the pharmaceutical compositions described herein to asubject in need thereof, wherein the administration is sufficient toachieve a reduction of about 0.224 annualized relapse rate relative tobaseline in the subject without substantially inducing one or more offlushing, abdominal pain, diarrhea, and nausea in the subject andwherein the administration does not require titration of thepharmaceutical composition. In one aspect, the subject experiences oneor more of flushing, abdominal pain, diarrhea, and nausea at anincidence rate of less than about 10%. In another aspect, the subject isa child. In one aspect, the child is over 9 years of age.

Another embodiment described herein is a pharmaceutical compositioncomprising any one of the pharmaceutical compositions described herein,for oral administration to a subject having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising a therapeutically effective amount ofone or more fumarate esters, wherein the subject achieves a reduction ofannualized relapse rate relative to baseline without substantiallyexperiencing one or more of flushing, abdominal pain, diarrhea, andnausea in the subject and wherein the administration does not requiretitration of the pharmaceutical composition.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, the method comprising the oral administration ofa therapeutically effective amount of one or more fumarate esterscomprising any one of the pharmaceutical compositions described herein,to a subject in need thereof, wherein the subject achieves a reductionof annualized relapse rate relative to baseline without substantiallyexperiencing one or more of flushing, abdominal pain, diarrhea, andnausea in the subject and wherein the administration does not requiretitration of the pharmaceutical composition.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising any of the compositions described herein foradministration to a subject having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising a therapeutically effective amount ofone or more fumarate esters, wherein the pharmaceutical composition isstable at 25° C. and 60% RH for at least 1 year.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising any of the compositions described hereincomprising a therapeutically effective amount of one or more fumarateesters for administration to a subject diagnosed with multiple sclerosisor psoriasis.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising orally administering to a subject inneed thereof a therapeutically effective amount of one or more fumarateesters comprising any of the pharmaceutical compositions describedherein.

Another embodiment described herein is a pharmaceutical compositioncomprising any one of the compositions described herein, for oraladministration to a subject of less than 17 years of age having ageneral autoimmune or neurodegenerative disorder, including but notlimited to multiple sclerosis or psoriasis, comprising a therapeuticallyeffective amount of one or more fumarate esters.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a subject of less than 17 years of agehaving a general autoimmune or neurodegenerative disorder, including butnot limited to multiple sclerosis or psoriasis, comprising orallyadministering to a subject in need thereof having an age less than 17 atherapeutically effective amount of one or more fumarate esterscomprising any one of the pharmaceutical compositions described herein.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising orally administering to a subject inneed thereof a therapeutically effective amount of a fumarate estercomprising any of the pharmaceutical compositions described herein and atherapeutically effective amount of a leukotriene receptor antagonist.In one aspect, the leukotriene receptor antagonist comprises montelukastor zafirlukast.

Another embodiment described herein is a pharmaceutical compositioncomprising a matrix fill comprising any of the compositions describedherein. In one aspect, the composition is shown in any of the tablesdescribed herein.

Another embodiment described herein is a pharmaceutical composition fortreating, retarding the progression of, delaying the onset of,prophylaxis of, amelioration of, or reducing the symptoms of a generalautoimmune or neurodegenerative disorder, including but not limited tomultiple sclerosis or psoriasis, comprising a fumarate ester, whereinthe pharmaceutical composition exhibits an in vitro dissolution rate (%dissolution per minute) at pH 6.8, as shown in any of the Drawingsdescribed herein.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising orally administering to a subject inneed thereof a therapeutically effective amount of one or more fumarateesters comprising any of the pharmaceutical compositions describedherein, wherein the composition exhibits an in vitro dissolution rate (%dissolution per minute) at pH 6.8, as shown in any of the Drawingsdescribed herein.

Another embodiment described herein is an oral pharmaceuticalcomposition for treating, retarding the progression of, delaying theonset of, prophylaxis of, amelioration of, or reducing the symptoms ofgeneral autoimmune or neurodegenerative disorders, including but notlimited to multiple sclerosis or psoriasis, comprising one or morefumarate esters, wherein the pharmaceutical composition exhibits aplasma monomethyl fumarate C_(max) of about 1321.3±618.9 ng/mL.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of general autoimmune or neurodegenerativedisorders, including but not limited to multiple sclerosis or psoriasis,comprising orally administering to a subject in need thereof atherapeutically effective amount of one or more fumarate esterscomprising any of the pharmaceutical compositions described herein,wherein the pharmaceutical composition exhibits a plasma monomethylfumarate C_(max) of about 1321.3±618.9 ng/mL.

Another embodiment described herein is an oral pharmaceuticalcomposition for treating, retarding the progression of, delaying theonset of, prophylaxis of, amelioration of, or reducing the symptoms ofgeneral autoimmune or neurodegenerative disorders, including but notlimited to multiple sclerosis or psoriasis, comprising one or morefumarate esters, wherein the pharmaceutical composition exhibits aplasma monomethyl fumarate C_(max) as shown herein in Drawing 15.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of general autoimmune or neurodegenerativedisorders, including but not limited to multiple sclerosis or psoriasis,comprising orally administering to a subject in need thereof atherapeutically effective amount of one or more fumarate esterscomprising any of the pharmaceutical compositions described herein,wherein the pharmaceutical composition exhibits a plasma monomethylfumarate pharmacokinetic parameter as described herein.

Another embodiment described herein is an oral pharmaceuticalcomposition for treating, retarding the progression of, delaying theonset of, prophylaxis of, amelioration of, or reducing the symptoms of ageneral autoimmune or neurodegenerative disorder, including but notlimited to multiple sclerosis or psoriasis, comprising one or morefumarate esters, wherein the pharmaceutical composition exhibits an invitro dissolution rate at pH 6.8 comprising about 10% to about 80%dissolution after about 10 minutes to about 480 minutes.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of general autoimmune or neurodegenerativedisorders, including but not limited to multiple sclerosis or psoriasis,comprising orally administering to a subject in need thereof atherapeutically effective amount of one or more fumarate esterscomprising any of the pharmaceutical compositions described herein,wherein the pharmaceutical composition is administered without titrationof the pharmaceutical composition and without substantially inducing oneor more of flushing, abdominal pain, diarrhea, and nausea in thesubject.

Another embodiment described herein is an oral pharmaceuticalcomposition for treating, retarding the progression of, delaying theonset of, prophylaxis of, amelioration of, or reducing the symptoms ofgeneral autoimmune or neurodegenerative disorders, comprising one ormore fumarate esters, wherein the pharmaceutical composition isadministered without titration of the pharmaceutical composition andwithout substantially inducing one or more of flushing, abdominal pain,diarrhea, and nausea in the subject.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising a controlled release soft capsule shellencapsulating a matrix comprising: about 10% to about 64% by weight ofone or more fumarate esters (FAE; PSD: d90≤100 μm); about 18% to about70% by weight of a mixture of mono- and di-glycerides; about 3% byweight of polyvinylpyrrolidone; about 10% by weight of polyoxyl 40hydrogenated castor oil, and about 5% by weight of lactic acid. In oneaspect, the matrix comprises about 13% to about 16%; about 27% to about32%; about 34%, about 48%, or about 53% to about 64%, each by weight ofone or more FAEs. In another aspect, the mixture of mono- anddi-glycerides is present in an amount of about 66% to about 69%; about48% to about 55%; or about 18% to about 29%, each by weight. In anotheraspect, the one or more FAEs comprise about 80 mg to about 460 mg FAE.In another aspect, the matrix comprises about 80 mg to about 105 mg FAE,about 90 mg to about 110 mg FAE, about 95 mg to about 115 mg FAE, about100 mg to about 120 mg FAE; about 180 mg to about 230 mg FAE; about 200mg to about 230 mg FAE; about 270 mg to about 360 mg FAE; about 340 mgto about 440 mg FAE; or about 400 to about 460 mg FAE. In anotheraspect, the matrix comprises about 90 mg to about 110 mg FAE. In anotheraspect, the matrix comprises about 180 mg to about 230 mg FAE. Inanother aspect, the matrix comprises about 200 mg to about 220 mg FAE.In another aspect, the matrix comprises about 214 mg FAE. In anotheraspect, the matrix comprises about 0.5 to about 3.5 mmol FAE. In anotheraspect, the matrix comprises about 0.6 to about 1.7 mmol FAE. In anotheraspect, the matrix comprises DMF, MMF, or a combination thereof. Inanother aspect, the matrix comprises DMF. In another aspect, the matrixcomprises MMF.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of a composition comprising one or morefumarate esters in an amount of about 90 mg to about 110 mg FAE or about170 mg to about 220 mg FAE, wherein the one or more doses comprise acontrolled release pharmaceutical composition that releases the contentsat a physiological pH of about pH 6.8.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of one or more fumarate esterscomprising about 90 mg to about 110 mg FAE or about 170 mg to about 220mg FAE wherein the FAE comprises dimethyl fumarate.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of one or more fumarate esterscomprising about 90 mg to about 110 mg FAE or about 170 mg to about 220mg FAE wherein the FAE comprises methyl hydrogen fumarate.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of one or more fumarate esters whereinmethyl hydrogen fumarate activates a nuclear erythroid 2-related factor2 (nuclear factor erythroid-derived 2-like 2; Nrf2) transcriptionalpathway. In one aspect, the dose comprises an oral controlled releasecomposition comprising: about 10% to about 64% by weight of one or morefumarate esters (FAE; PSD: d90≤100 μm); about 18% to about 70% by weightof a mixture of mono- and di-glycerides; about 3% by weight ofpolyvinylpyrrolidone; about 10% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid. In another aspect,the dose comprises one or more FAEs in an amount of about 80 mg to about460 mg. In another aspect, the dose comprises one or more FAEs in anamount of about 85 mg to about 110 mg. In another aspect, the dosecomprises one or more FAEs in an amount of about 170 mg to about 220 mg.In another aspect, a daily total dose comprises one or more FAEs in anamount of about 340 mg to about 440 mg. In another aspect, the fumarateester comprises MMF, DMF, or a combination thereof. In another aspect,the matrix comprises DMF. In another aspect, the fumarate estercomprises MMF.

Another embodiment described herein is an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 10% to about 64% by weight of one or moreFAEs (PSD: d90≤100 μm); about 18% to about 70% by weight of a mixture ofmono- and di-glycerides; about 1% to about 10% by weightpolyvinylpyrrolidone; about 2% to about 10% by weight polyoxyl 40hydrogenated castor oil, and about 1% to about 5% by weight lactic acid.In one aspect, the soft capsule shell is a soft capsule comprising about30% by weight of gelatin; about 10% by weight of methylacrylic acidcopolymer; about 18% by weight of glycerol; about 1% by weight oftriethyl citrate; about 1.5% by weight of ammonia; and about 37% byweight of water.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 10% to about 64% by weight of one or morefumarate esters (FAE; PSD: d90≤100 μm); about 18% to about 70% by weightof a mixture of mono- and di-glycerides; about 1% to about 10% by weightpolyvinylpyrrolidone; about 2% to about 10% by weight polyoxyl 40hydrogenated castor oil, and about 1% to about 5% by weight lactic acid.

Another embodiment described herein is an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 34% by weight of FAE; about 48% by weight ofa mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid. In one aspect, thesoft capsule shell is a soft capsule shell comprising about 30% byweight of gelatin; about 10% by weight of methylacrylic acid copolymer;about 18% by weight of glycerol; about 1% by weight of triethyl citrate;about 1.5% by weight of ammonia; and about 37% by weight of water.

Another embodiment described herein is method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 34% by weight of FAE; about 48% by weight ofa mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 34% by weight of DMF or MMF; about 48% byweight of a mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid.

Another embodiment described herein is an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 75 mg, about 80 mg, about 85 mg, about 90mg, about 95 mg, about 100 mg, about 105 mg, about 108 mg, about 110 mg,about 115 mg, about 120 mg, about 180 mg, about 200 mg, about 210 mg,about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg,about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, orabout 480 mg of FAE; about 48% by weight of a mixture of mono- anddi-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% byweight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight oflactic acid.

Another embodiment described herein is an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 75 mg, about 80 mg, about 85 mg, about 90mg, about 95 mg, about 100 mg, about 105 mg, about 108 mg, about 110 mg,about 115 mg, about 120 mg, about 180 mg, about 200 mg, about 210 mg,about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg,about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, orabout 480 mg of DMF or MMF; about 48% by weight of a mixture of mono-and di-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3%by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weightof lactic acid.

Another embodiment described herein is an oral controlled releasepharmaceutical composition dosage form comprising a daily total amountof FAE of about 180 mg, about 200 mg, about 210 mg, about 216 mg, about220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg.

Another embodiment described herein is an oral controlled releasepharmaceutical composition dosage form comprising a daily total amountof DMF or MMF of about 180 mg, about 200 mg, about 210 mg, about 216 mg,about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg,about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg.

Another embodiment described herein is an oral pharmaceuticalcomposition providing a daily total amount of DMF or MMF of about 180mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230mg, about 240 mg, about 360 mg, about 400 mg, about 420 mg, about 432mg, about 440 mg, about 460 mg, or about 480 mg DMF or MMF; about 48% byweight of a mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of a pharmaceutical compositionproviding a daily total amount of FAE of about 180 mg, about 200 mg,about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg,about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg,about 460 mg, or about 480 mg.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of a pharmaceutical compositionproviding a daily total amount of DMF or MMF of about 180 mg, about 200mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440mg, about 460 mg, or about 480 mg.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising a controlled release soft capsule shell andmatrix comprising: about 10% to about 64% of one or more fumarate esters(FAE; PSD: <100 μm); about 18% to about 70% by weight of a mixture ofmono- and di-glycerides; at least about 3% by weight ofpolyvinylpyrrolidone; at least about 10% by weight of polyoxyl 40hydrogenated castor oil, and at least about 5% by weight of lactic acid.In one aspect, the composition comprises one or more FAEs in an amountof about 13% to about 16% by weight; about 27% to about 32% by weight;or about 48% to about 64% by weight. In another aspect, the compositioncomprises mono- and di-glycerides in an amount of about 66% to about 69%by weight; about 50% to about 55% by weight; or about 18% to about 29%by weight. In another aspect, the composition comprises one or more FAEsin an amount of about 80 mg to about 460 mg FAE. In another aspect, thecomposition comprises one or more FAEs in an amount of about 80 mg toabout 100 mg FAE; about 90 mg to about 110 mg FAE, about 100 mg to about120 mg FAE; about 180 mg to about 220 mg FAE; about 200 mg to about 230mg FAE; or about 400 mg to about 460 mg FAE. In another aspect, thecomposition comprises one or more FAEs in an amount of about 90 mg toabout 110 mg FAE. In another aspect, the composition comprises one ormore FAEs in an amount of about 100 mg to about 120 mg FAE. In anotheraspect, the composition comprises one or more FAEs in an amount of about200 mg to about 220 mg FAE. In another aspect, the composition comprisesone or more FAEs in an amount of about 210 mg to about 220 mg FAE. Inanother aspect, the composition comprises one or more FAEs in an amountof about 214 mg FAE. In another aspect, the composition comprises one ormore FAEs in an amount of about 1.5 to about 1.7 mmol FAE. In anotheraspect, the matrix comprises DMF, MMF, or a combination thereof. Inanother aspect, the matrix comprises DMF. In another aspect, the matrixcomprises MMF.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of one or more fumarate esters in anamount of about 180 mg to about 220 mg FAE, wherein the one or moredoses comprise a controlled release pharmaceutical composition thatreleases the contents at a physiological pH of about pH 6.8.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of one or more fumarate esters in anamount of about 180 mg to about 220 mg FAE, wherein the FAE comprisesdimethyl fumarate.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of one or more fumarate esters in anamount of about 180 mg to about 220 mg FAE, wherein the FAE comprisesmethyl hydrogen fumarate.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of one or more fumarate esters whereinmethyl hydrogen fumarate activates a nuclear erythroid 2-related factor2 (nuclear factor erythroid-derived 2-like 2; Nrf2) transcriptionalpathway. In one aspect, the one or more doses of fumarate esterscomprise an oral controlled release composition comprising: about 10% toabout 64% by weight of one or more fumarate esters (FAE; PSD: <100 μm);about 18% to about 70% by weight of a mixture of mono- anddi-glycerides; at least about 3% by weight polyvinylpyrrolidone; atleast about 10% by weight polyoxyl 40 hydrogenated castor oil, and atleast about 5% by weight lactic acid. In another aspect, the dosecomprises one or more FAEs in an amount of about 80 mg to about 460 mg.In another aspect, the dose comprises one or more FAEs in an amount ofabout 85 mg to about 110 mg. In another aspect, the dose comprises oneor more FAEs in an amount of about 170 mg to about 220 mg. In anotheraspect, a daily total dose comprises one or more FAEs in an amount ofabout 340 mg to about 440 mg. In another aspect, the FAE comprises MMF,DMF, or a combination thereof. In another aspect, the FAE comprises DMF.In another aspect, the FAE comprises MMF.

Another embodiment described herein is an oral controlled releasepharmaceutical composition comprising a soft capsule and a matrix, thematrix comprising about 10% to about 64% by weight of one or morefumarate esters (FAE; PSD: d90≤100 μm); about 18% to about 70% by weightof a mixture of mono- and di-glycerides; about 1% to about 10% by weightpolyvinylpyrrolidone; about 2% to about 10% by weight polyoxyl 40hydrogenated castor oil, and about 1% to about 5% by weight lactic acid.In one embodiment, the FAE is dimethyl fumarate. In one embodiment, thesoft capsule is a soft capsule shell comprising about 30% by weight ofgelatin; about 10% by weight of methylacrylic acid copolymer; about 18%by weight of glycerol; about 1% by weight of triethyl citrate; about1.5% by weight of ammonia; and about 37% by weight of water.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 10% to about 64% by weight of one or morefumarate esters (FAE; PSD: d90≤100 μm); about 18% to about 70% by weightof a mixture of mono- and di-glycerides; about 1% to about 10% by weightpolyvinylpyrrolidone; about 2% to about 10% by weight polyoxyl 40hydrogenated castor oil, and about 1% to about 5% by weight lactic acid.

Another embodiment described herein is an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 34% by weight of FAE; about 48% by weight ofa mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid. In one embodiment,the FAE is dimethyl fumarate. In one embodiment, the soft capsule is asoft capsule comprising about 30% by weight of gelatin; about 10% byweight of methylacrylic acid copolymer; about 18% by weight of glycerol;about 1% by weight of triethyl citrate; about 1.5% by weight of ammonia;and about 37% by weight of water.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 34% by weight of FAE; about 48% by weight ofa mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 34% by weight of DMF or MMF; about 48% byweight of a mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid.

Another embodiment described herein is an oral controlled releasepharmaceutical composition comprising a soft capsule and a matrix, thematrix comprising about 75 mg, about 80 mg, about 85 mg, about 90 mg,about 95 mg, about 100 mg, about 105 mg, about 108 mg, about 110 mg,about 115 mg, about 120 mg, about 180 mg, about 200 mg, about 210 mg,about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg,about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, orabout 480 mg of FAE and about 48% by weight of a mixture of mono- anddi-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% byweight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight oflactic acid. In one embodiment, the soft capsule is a soft capsulecomprising about 30% by weight of gelatin; about 10% by weight ofmethylacrylic acid copolymer; about 18% by weight of glycerol; about 1%by weight of triethyl citrate; about 1.5% by weight of ammonia; andabout 37% by weight of water.

Another embodiment described herein is an oral controlled releasepharmaceutical composition comprising a soft capsule and a matrix, thematrix comprising about 75 mg, about 80 mg, about 85 mg, about 90 mg,about 95 mg, about 100 mg, about 105 mg, about 108 mg, about 110 mg,about 115 mg, about 120 mg, about 180 mg, about 200 mg, about 210 mg,about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg,about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, orabout 480 mg of DMF or MMF and about 48% by weight of a mixture of mono-and di-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3%by weight of polyoxyl 40 hydrogenated castor oil, and about 5% by weightof lactic acid. In one embodiment, the soft capsule is a soft capsulecomprising about 30% by weight of gelatin; about 10% by weight ofmethylacrylic acid copolymer; about 18% by weight of glycerol; about 1%by weight of triethyl citrate; about 1.5% by weight of ammonia; andabout 37% by weight of water.

Another embodiment described herein is an oral controlled releasepharmaceutical composition dosage forms comprising a daily total amountof FAE of about 180 mg, about 200 mg, about 210 mg, about 216 mg, about220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg.

Another embodiment described herein is an oral controlled releasepharmaceutical composition dosage form comprising a daily total amountof DMF or MMF of about 180 mg, about 200 mg, about 210 mg, about 216 mg,about 220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg,about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg.

Another embodiment described herein is an oral pharmaceuticalcompositions providing a daily total amount of FAE of about 180 mg,about 190 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg,about 230 mg, about 240 mg, about 360 mg, about 380 mg, about 400 mg,about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mgFAE; about 48% by weight of a mixture of mono- and di-glycerides; about10% by weight of polyvinylpyrrolidone; about 3% by weight of polyoxyl 40hydrogenated castor oil, and about 5% by weight of lactic acid.

Another embodiment described herein is an oral pharmaceuticalcompositions providing a daily total amount of DMF or MMF of about 180mg, about 190 mg, about 200 mg, about 210 mg, about 216 mg, about 220mg, about 230 mg, about 240 mg, about 360 mg, about 380 mg, about 400mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480mg DMF or MMF; about 48% by weight of a mixture of mono- anddi-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% byweight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight oflactic acid.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of a pharmaceutical compositionproviding a daily total amount of FAE of about 180 mg, about 200 mg,about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg,about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg,about 460 mg, or about 480 mg. In one embodiment, the pharmaceuticalcomposition comprises about 34% by weight of FAE; about 48% by weight ofa mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil; and about 5% by weight of lactic acid.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of a pharmaceutical compositionproviding a daily total amount of DMF or MMF of about 180 mg, about 200mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440mg, about 460 mg, or about 480 mg. In one embodiment, the pharmaceuticalcomposition comprises about 34% by weight of DMF or MMF; about 48% byweight of a mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil; and about 5% by weight of lactic acid.

Another embodiment described herein is an oral pharmaceuticalcomposition for treating multiple sclerosis in a subject in need thereofcomprising one or more fumarate esters comprising DMF, MMF, or acombination thereof.

Another embodiment described herein is an oral pharmaceuticalcomposition for treating multiple sclerosis in a subject in need thereofcomprising one or more fumarate esters comprising DMF.

Another embodiment described herein is an oral pharmaceuticalcomposition for treating multiple sclerosis in a subject in need thereofcomprising one or more fumarate esters comprising MMF.

Another embodiment described herein is any of the foregoing compositionsor methods, wherein the fumarate ester comprises a therapeuticallyeffective amount of DMF, MMF, or a combination thereof.

Another embodiment described herein is any of the foregoing compositionsor methods, wherein the fumarate ester comprises a therapeuticallyeffective amount of DMF.

Another embodiment described herein is any of the foregoing compositionsor methods, wherein the fumarate ester comprises a therapeuticallyeffective amount of MMF.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features of the present disclosure will become more apparentwith the following detailed description when taken with reference to theaccompanying drawings, each according to an aspect of the presentdisclosure: FIG. 1. Scheme for manufacturing enteric soft capsulescomprising a DMF matrix.

FIG. 2. Dissolution of enteric soft capsules comprising two DMFformulations.

FIG. 3. DMF enteric soft capsule stability.

FIG. 4. DMF release in enteric soft capsules.

FIG. 5. Surfactant affects DMF release rate.

FIG. 6. Polyvinylpyrrolidone concentration affects DMF release rate.

FIG. 7. DMF enteric soft capsules are amenable to controlled or extendedrelease.

FIG. 8. DMF particle size affects release rate.

FIG. 9. Two-stage dissolution of application batches.

FIG. 10. Two-stage dissolution of GMP batch compared to applicationbatches.

FIG. 11. Effects of Povidone K30 and PEG 600 on DMF release rate.

FIG. 12. Two-stage dissolution of 120 mg DMF enteric soft capsule.

FIG. 13. DMF enteric soft capsule stability at T₀ and after 3- and6-month conditions.

FIG. 14. Two-stage dissolution of monomethyl fumarate enteric softcapsules.

FIG. 15. Mean plasma concentration of MMF over time following doseadministration.

FIG. 16. Two-stage dissolution of dimethyl fumarate and monomethylfumarate enteric soft capsules.

FIG. 17. Release of fumarate ester in soybean oil from enteric softcapsules under acidic conditions (pH 1.2).

FIG. 18. Release of fumarate ester in soybean and vegetable oil fromenteric soft capsules under acidic conditions (pH 1.2).

FIG. 19. Release of fumarate ester in mono- and di-glycerides fromenteric soft capsules under acidic conditions (pH 1.2).

FIG. 20. Two-stage dissolution of fumarate ester in soft capsules coatedwith an enteric coating.

FIG. 21. Two-stage dissolution of fumarate ester in soft capsules andenteric soft capsules coated with an enteric coating.

FIG. 22. Comparison of data from FIG. 21 with enteric soft capsulecontaining dimethyl fumarate.

FIG. 23. Two-stage dissolution of fumarate ester in a soft capsule andan enteric soft capsule coated with an enteric coating with and withoutprecoating.

FIG. 24A-B. Mean plasma monomethyl fumarate concentrations for Testsamples T1, T2, T3, and the Reference as a function of time after dosing(see Examples 31-33). FIG. 24A and FIG. 24B show the same data, withFIG. 24B having a logarithmic y-axis.

FIG. 25A-B. Mean plasma monomethyl fumarate concentrations for Testsamples T4, T5, T6, and the Reference as a function of time after dosing(see Examples 31-33). FIG. 25A and FIG. 25B show the same data, withFIG. 25B having a logarithmic y-axis.

DETAILED DESCRIPTION

Described herein are pharmaceutical compositions of fumarate esters,such as dimethyl fumarate, monomethyl fumarate, pro-drugs of monomethylfumarate, other pharmacologically active fumarate esters, orcombinations thereof.

The pharmaceutical compositions described herein provide compositions offumarate esters, di-alkyl fumarates, mono-alkyl fumarates, such asdimethyl fumarate, monomethyl fumarate, or combinations thereof, andmethods for preparation thereof. Also described herein are compositionsand methods for manufacturing controlled, delayed, or extended releasefumarate esters, dimethyl fumarate, monomethyl fumarate, or combinationsthereof as capsule dosage forms. In one embodiment described herein, thefumarate ester pharmaceutical composition is a liquid. In one aspect,the liquid is a single-phase, flowable liquid. The liquid can be lipid,lipophilic, hydrophilic, or combinations thereof. In one aspect, theliquid is non-aqueous. In another aspect, the liquid is aqueous. In oneembodiment described herein, the fumarate ester pharmaceuticalcomposition is a liquid encapsulated within a soft capsule shell. Inanother embodiment described herein, the fumarate ester pharmaceuticalcomposition is a liquid encapsulated within a hard capsule shell. Inanother embodiment, the soft capsule is a soft capsule or an entericsoft capsule coated with an enteric coating and one or more subcoatingsor top coatings. In another embodiment described herein, the compositionis encapsulated in a hard capsule or an enteric hard capsule. In anotherembodiment described herein, the composition is encapsulated in a hardcapsule comprising an enteric coating and one or more subcoatings or topcoatings. In another embodiment described herein, the fumarate ester isin the form of solid microparticles of defined size within a compositioncomprising a lipid or lipophilic vehicle. In some aspects describedherein, the lipid or lipophilic vehicle may comprise one or morehydrophilic polymers or species, but as described herein, the vehicle isconsidered a lipid or lipophilic vehicle.

As used herein, the terms “fumarate ester” or “FAE” refers to anypharmacologically active mono- or di-alkyl fumarate ester, such asmonomethyl fumarate, dimethyl fumarate, or other fumarate esters, acids,salts, pro-drugs of monomethyl fumarate, derivatives thereof,combinations or mixtures of any of the foregoing. Fumarate ester as usedherein also comprises prodrugs that are metabolized to monomethylfumarate after administration to a subject.

The terms “active ingredient” or “active pharmaceutical ingredient” asused herein refer to a pharmaceutical agent, active ingredient,compound, or substance, compositions, or mixtures thereof, that providea pharmacological, often beneficial, effect.

The term “dose” as used herein denotes any form of the active ingredientformulation that contains an amount sufficient to produce a therapeuticeffect with a single administration.

The term “dosage” as used herein refers to the administering of aspecific amount, number, and frequency of doses over a specified periodof time, typically 1 day.

The term “dosage form” as used herein refers to any pharmaceuticalcomposition described herein in a form that can be administered to asubject. The dosage form used herein is for oral administration.Exemplary dosage forms described herein include capsules, hard capsules,soft capsules, enteric soft capsules, coated soft capsules, suspensions,solutions emulsions, or the like.

The term “soft capsule” or “soft gel capsule” as used herein refers to asoft capsule comprising one or more film-forming polymers that iscapable of encapsulating a liquid “matrix” or “fill” comprisingpharmaceutically acceptable excipients and one or more activepharmaceutical ingredients. The term soft capsule can encompass entericsoft capsules as described herein.

The term “enteric soft capsule” as used herein refers to a soft capsulecomprising one or more enteric polymers in the shell or a soft capsulethat has been coated with one or more enteric coatings that are appliedto the external surface of the capsule as described herein. The coatedsoft capsule may have one or more subcoatings applied prior to theapplication of the enteric coating.

The terms “matrix,” “fill,” or “matrix fill” as used herein refer to acomposition comprising one or more active pharmaceutical ingredientsthat is encapsulated within a capsule. Often the matrix comprises avehicle, one or more active pharmaceutical ingredients, and one or morepharmaceutically acceptable excipients. In one aspect described herein,the matrix is a liquid and comprises a lipid or lipophilic liquidcomprising one or more fumarate esters.

The terms “active pharmaceutical ingredient load” or “drug load” as usedherein refers to the quantity (mass) of the active pharmaceuticalingredient comprised in a single soft capsule fill.

The terms “formulation” or “composition” as used herein refers to thedrug in combination with pharmaceutically acceptable excipients. Thisterm includes orally administrable formulations as well as formulationsadministrable by other means.

The term “titration” as used herein refers to the incremental increasein drug dosage to a level that provides the optimal therapeutic effect.

The term “controlled release” as used herein encompasses the terms“immediate release,” “modified release,” “sustained release,” “extendedrelease,” and “delayed release.”

The terms “extended release” or “sustained release” as used hereinrefers to a composition that releases an active ingredient according toa desired profile over an extended period under physiological conditionsor in an in vitro test. By “extended period” it is meant a continuousperiod of time of at least about 1 hour; about 2 hours; about 4 hours;about 6 hours; about 8 hours; about 10 hours; about 12 hours; about 14hours; about 16 hours; about 18 hours; about 20 hours about 24 hours; oreven longer; specifically, over a period of about 18 hours underphysiological conditions or in an in vitro assay.

The term “modified release” as used herein refers to a composition thatreleases an active ingredient at a slower rate than does an immediaterelease formulation under physiological conditions or in an in vitrotest.

The term “delayed” release” as used herein refers to a composition thatreleases an active ingredient after a period of time, for exampleminutes or hours, such that the active ingredient is not releasedinitially. A delayed release composition may provide, for example, therelease of a drug or active ingredient from a dosage form, after acertain period, under physiological conditions or in an in vitro test.

The term mean “particle size distribution” (PSD) as used herein refersto the mean particle size from a statistical distribution of a range ofparticle sizes as described herein. The distribution may be a Gaussian,normal distribution, or a non-normal distribution.

The terms such as “d90,” “d50,” and “d10” refer to the percentage (e.g.,90%, 50%, or 10%, respectively) of particle sizes that are less than aspecified size, range, or distribution. For example, “d90≤90 μm” asspecified means that 90% of the particle sizes within a distribution ofparticles are less than or equal to 90 μm.

The term “C_(max)” as used herein refers to the maximum observed blood(plasma, serum, or whole blood) concentration or the maximum bloodconcentration calculated or estimated from a concentration to timecurve, and is expressed in units of mg/L or ng/mL, as applicable.

The term “C_(min)” as used herein refers to the minimum observed blood(plasma, serum, or whole blood) concentration or the minimum bloodconcentration calculated or estimated from a concentration to timecurve, and is expressed in units of mg/L or ng/mL, as applicable.

The term “C_(avg)” as used herein refers to the blood (plasma, serum, orwhole blood) concentration of the drug within the dosing interval, iscalculated as AUC/dosing interval, and is expressed in units of mg/L orng/mL, as applicable.

The term “T_(max)” as used herein refers to the time afteradministration at which C_(max) occurs, and is expressed in units ofhours (h) or minutes (min), as applicable.

The term “AUC_(0→τ)” as used herein refers to area under the blood(plasma, serum, or whole blood) concentration versus time curve fromtime zero to time tau (i) over a dosing interval at steady state, wheretau is the length of the dosing interval, and is expressed in units ofh·mg/L or h·ng/mL, as applicable. For example, the term AUC_(0→12) asused herein refers to the area under the concentration versus time curvefrom 0 to 12 hours.

The term “AUC_(0→∞)” as used herein refers to the area under the blood(plasma, serum, or whole blood) concentration versus time curve fromtime 0 hours to infinity, and is expressed in units of h·mg/L orh·ng/mL, as applicable.

The term “AUC_(overall)” as used herein refers to the combined areaunder the blood (plasma, serum, or whole blood) concentration versustime curve, and is expressed in units of h·mg/L (or h·ng/mL) for atleast one or more doses of the pharmaceutical compositions describedherein. In one aspect, the “AUC_(overall)” refers to the combined areaunder the blood concentration versus time curve for at least two dosesof the pharmaceutical compositions described herein.

The terms “bioequivalence” or “bioequivalent” as used herein refer to adrug product or dosage form that has highly similar release and systemicabsorption as compared to a reference drug. The U.S. Food, Drug andCosmetic Act (21 U.S.C. § 505(j)(8)(B)(i)) provides that a drug isbioequivalent to a reference listed drug (RLD) if: “the rate and extentof absorption of the drug do not show a significant difference from therate and extent of absorption of the listed drug when administered atthe same molar dose of the therapeutic ingredient under similarexperimental conditions in either a single dose or multiple doses . . ..”

The phrase “enhanced bioavailability” as used herein refers to theincreased proportion of an active pharmaceutical ingredient that entersthe systemic circulation when introduced into the body as compared to areference active pharmaceutical's bioavailability. Bioavailability canbe determined by comparing the rate and extent of absorption of a testdrug with a reference drug when administered at the same molar dose ofthe active therapeutic ingredient under similar experimental conditionsin either a single dose or multiple doses. Typical pharmacokineticparameters can be used to demonstrate enhanced bioavailability comparedto the reference.

The term “treating” refers to administering a therapy in an amount,manner, or mode effective (e.g., a therapeutic effect) to improve acondition, symptom, disorder, or parameter associated with a disorder,or a likelihood thereof.

The term “prophylaxis” refers to preventing or reducing the progressionof a disorder, either to a statistically significant degree or to adegree detectable to one skilled in the art.

The term “substantially” as used herein means to a great or significantextent, but not completely.

As used herein, all percentages (%) refer to weight percent (w/w) unlessnoted otherwise.

The term “about” as used herein refers to any values, including bothintegers and fractional components that are within a variation of up to±10% of the value modified by the term “about.”

As used herein, “a” or “an” means one or more unless otherwisespecified.

Terms such as “include,” “including,” “contain,” “containing,” “having,”and the like mean “comprising.”

The term “or” can be conjunctive or disjunctive.

One embodiment described herein is a liquid pharmaceutical compositionof one or more fumarate esters. Particles or micronized powders of oneor more fumarate esters can be suspended or solvated in varioussolutions. The solutions can comprise lipid or lipophilic liquids orhydrophilic liquids. Such liquids can be encapsulated in capsules, suchas hard or soft capsules. In one embodiment, the pharmaceuticalcomposition comprises a non-aqueous, single-phase, flowable liquid. Inone embodiment, the pharmaceutical composition comprises a liquidcomprising one or more lipid liquids, lipophilic liquids, hydrophilicliquids, or a combination thereof. In one embodiment, the pharmaceuticalcomposition comprises a liquid comprising one or more lipid liquids,lipophilic liquids, or a combination thereof. In one embodiment, thepharmaceutical composition comprises a liquid comprising one or morelipophilic liquids, hydrophilic liquids, or a combination thereof. Inone embodiment, the pharmaceutical composition comprises a liquidcomprising one or more lipid liquids.

One embodiment described herein, is a controlled release pharmaceuticalcomposition comprising one or more fumarate esters. Another embodimentis a controlled release pharmaceutical composition comprising a softcapsule shell encapsulating a liquid matrix fill comprising one or morefumarate esters. Another embodiment is a controlled releasepharmaceutical composition comprising a hard capsule shell encapsulatinga liquid matrix fill comprising one or more fumarate esters.

Another embodiment is a controlled release pharmaceutical compositioncomprising a capsule shell encapsulating a matrix fill comprising one ormore fumarate esters, wherein the capsule shell comprises one or moresubcoatings, coatings, or topcoatings. Suitable coatings may beadherence coatings, enteric coatings, moisture barriers, air or gasbarriers, polymer coatings, colorings, flavors, writings, orcombinations thereof.

In one embodiment, the pharmaceutical composition has controlled releaseproperties.

In another embodiment, the matrix fill provides controlled releaseproperties. Such controlled release matrix fills are described inInternational patent Application Publication No. WO 2005/009409; U.S.Patent Application Publication No. US 2006/0115527; U.S. Pat. Nos.8,293,270; and 8,333,989, each of which is incorporated by referenceherein for such teachings. In one aspect, the matrix is configured toprovide controlled release, extended release, sustained release, delayedrelease, or combinations thereof.

In another embodiment, the matrix comprises a lipid or lipophilicvehicle that provides a suspension of fumarate ester microparticleshaving defined sizes. In one aspect, a capsule comprising a lipid orlipophilic vehicle comprising suspension of one or more fumarate estermicroparticles provides controlled release delivery of the fumarateester. In one embodiment, the capsule is a soft capsule. In anotherembodiment, the capsule is a hard capsule. In another embodiment, thecapsule is coated with one or more subcoatings, one or more entericcoatings, and one or more topcoating moisture barriers.

The fumarate ester particles described herein (e.g., dimethyl fumarateor monomethyl fumarate, or prodrugs of monomethyl fumarate) may begenerated by any particle size reduction or particle growth methodologyknown to one having ordinary skill the art. Exemplary and non-limitingmethods may comprise a “top-down” reduction in particle size includingmechanical micronization techniques, wherein a larger particle iscrushed, bashed, or ground into a smaller particle through techniques,such as jet milling, ball milling, or high pressure homogenization; orparticle engineering techniques such as cryogenic spraying or crystalengineering. In addition, “bottom-up” processing may be used to build asuitable size of particles as described herein using dualsolvent/anti-solvent rapid precipitation techniques. See, Handbook ofPharmaceutical Granulation Technology, CRC Press, 3^(rd) Edition, 2010,which is incorporated by reference herein for teachings related togenerating pharmaceutical particles. In one aspect described herein,fumarate ester particles of a specified size distribution are produceusing a milling technique.

In another embodiment, the pharmaceutical composition comprises liquidmatrix fills for fumarate esters, such as dimethyl fumarate, monomethylfumarate, prodrugs thereof, or derivatives thereof, based on lipids orlipophilic vehicles or hydrophilic vehicles. Some of the describedmatrices have a hydrophobic (lipophilic) surface in contact with thehydrophilic soft capsule shell to minimize any potential shell-fillinteractions, such as when soft capsules are filled with hydrophilicvehicles.

Described herein are methods for manufacturing liquid matrix fillscomprising fumarate esters, such as dimethyl fumarate, monomethylfumarate, prodrugs thereof, or derivatives thereof, in a controlledrelease soft capsule in the form of a suspension, where part or all ofthe fumarate ester is suspended within the matrix. Also provided arecompositions and formulations where the fumarate ester is incorporatedinto a one-phase or two-phase matrix.

Also described herein are methods for manufacturing liquid matrix fillscomprising fumarate esters or derivatives thereof, in a delayed releasesoft capsule in the form of a suspension, where part or all of thefumarate ester is suspended within the matrix.

Described herein are methods for manufacturing liquid matrix fillscomprising fumarate esters or derivatives thereof, in an extendedrelease soft capsule in the form of a suspension, where part or all ofthe fumarate ester is suspended within the matrix.

Another embodiment described herein is a controlled, delayed, orextended release capsule having a shell and a matrix fill, wherein thematrix fill includes a lipid or lipophilic liquid vehicle comprising asuspension of solid particles of one or more fumarate esters such asdimethyl fumarate, monomethyl fumarate, prodrugs thereof, or derivativesthereof. In another embodiment, the lipid or lipophilic vehiclecomprises an oil, a vegetable oil, fatty acid, fatty acid ester, or acombination thereof. In one embodiment, the matrix fill is a singlephase lipid or lipophilic liquid at room temperature and preventssublimation of the fumarate ester. In another embodiment, the lipid orlipophilic liquid vehicle comprises one or more oils, mono/diglycerides,polyoxyl hydrogenated castor oils, polyvinylpyrrolidones, or acombination thereof. In another embodiment, the lipid or lipophilicliquid vehicle comprises an oil. In another embodiment, the lipid orlipophilic vehicle comprises mono/diglycerides, polyoxyl hydrogenatedcastor oils, polyvinylpyrrolidones, or a combination thereof.

Exemplary lipid or lipophilic vehicles comprise mineral oil; lightmineral oil; natural oils (e.g., vegetable, corn, canola, sunflower,soybean, olive, coconut, cocoa, peanut, almond, cottonseed, persic,sesame, squalane, castor, cod liver) hydrogenated vegetable oil;partially hydrogenated oils; beeswax; polyethoxylated beeswax; paraffin;normal waxes; medium chain medium chain monoglycerides, diglycerides andtriglycerides; higher aliphatic alcohols; higher aliphatic acids; longchain fatty acids; saturated or unsaturated fatty acids; hydrogenatedfatty acids; fatty acid glycerides; polyoxyethylated oleic glycerides;monoglycerides and diglycerides; mono-, bi- or tri-substitutedglycerides; glycerol mono-oleate esters; glycerol mono-caprate; glycerylmonocaprylate; propylene glycol dicaprylate; propylene glycolmonolaurate; glyceryl palmitostearate; glyceryl behenate;diethyleneglycol palmitostearate; polyethyleneglycol stearate;polyoxyethyleneglycol palmitostearate; glyceryl mono palmitostearate;cetyl palmitate; polyethyleneglycol palmitostearate;dimethylpolysiloxane; mono- or di-glyceryl behenate; fatty alcoholsassociated with polyethoxylate fatty alcohols; cetyl alcohol; octyldodecanol; myristyl alcohol; isopropyl myristate, isopropyl palmitate,stearic acid, or stearyl alcohol, inter alia, or combinations thereof.In one embodiment, the liquid matrix comprises solid particles offumarate ester suspended in a lipid or lipophilic vehicle of vegetableoil, fatty acid, fatty acid ester, or a combination thereof. In oneembodiment, the lipid or lipophilic vehicle is a liquid at roomtemperature (e.g., 25° C.) or phisiological temperature (e.g., 37° C.).In one embodiment, the lipid or lipophilic vehicle is soybean oil. Inanother embodiment, the lipid or lipophilic vehicle comprises mediumchain monoglycerides and diglycerides.

In one embodiment, the matrix comprises a solvent or solubilityenhancing agent. Exemplary solvents or solubility enhancing agentsuseful for the matrix fills described herein include Capmul® MCM,Cremophor® RH 40, Captex® 355, Croscarmellose, Crospovidone,Crospovidone CL, Crospovidone CL-F, Crospovidone CL-M, Imwitor® 742,Kollidon® CL, Kollidon® CL-F, Kollidon® CL-M, Labrafac™ Lipophile WL1349, Labrafil® M2125CS, Labrasol®, Lutrol® F 68, Maisine™ 35-1,mannitol, Miglyol® 812, Pearlitol® Flash, Peceol®, polyethylene glycol400, polyethylene glycol 600, polyethylene glycol 3350, Plurol® OleiqueCC 497, Povidone K 17, Povidone K 30, propylene glycol, or combinationsthereof. In one embodiment, the lipid or lipophilic vehicle comprisesmedium chain mono- and diglycerides (e.g., Capmul® MCM) and polyoxyl 40hydrogenated castor oil (e.g., macrogolglycerol hydroxystearate;Cremophor® RH 40).

In another embodiment, the matrix comprises a one or more hydrophilicsolvents or suspension agents. The matrix can polyvinylpyrrolidone,polyethylene glycols of molecular weight ranging from about 200 to about8000 (M_(N), number average molecular weight), or combinations thereof.In one embodiment, the matrix comprises polyvinylpyrrolidone K30 (e.g.,Povidone K30). In another embodiment, the matrix comprises polyethyleneglycol 400 and poly polyvinylpyrrolidone K30.

In another embodiment, the matrix fill comprises a release regulatorsuch as a fatty acid salt, fatty acid ester, or fatty acidpolyoxyethylene derivative. The release regulator can also be asurfactant having a hydrophilic/lipophilic balance (HLB) value betweenabout 2 and about 40. The HLB characteristic of surfactants can bedetermined in accordance with “Physical Pharmacy: Physical ChemicalPrinciples in the Pharmaceutical Sciences,” Fourth Edition, pp. 371-373,A. Martin, Ed., Lippincott Williams & Wilkins, Philadelphia (1993),which is incorporated by reference herein for such teachings.

In another embodiment, the matrix comprises emulsifying or solubilizingagents such as acacia, cholesterol, diethanolamine, glycerylmonostearate, lanolin alcohols, lecithin, mono- and di-glycerides,monoethanolamines, oleic acids, oleyl alcohols, poloxamer,polyoxyethylene 50 stearate, polyoxyl 35 castor oil, polyoxyl 40hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 80, propylene glycol diacetate, propyleneglycol monostearate, sodium lauryl sulfate, sodium stearate, sorbitanmonolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, stearic acid, trolamine, emulsifying wax, or combinationsthereof.

In another embodiment, the matrix comprises a neutralizing agent.Without being bound to any theory, the neutralizing agent it thought tostabilize the fumarate ester in the matrix fill by preventinghydrolysis. In addition, without being bound by any theory, theneutralizing agent may stabilize soft capsule shells comprising entericpolymers such as acrylate methacrylate by forming salts with themethylacrylate moieties from the capsule shell. In one aspect, theneutralizing agent comprises an organic acid, ester, or salt. In anotheraspect, the neutralizing agent comprises at least one of lactate,fumarate, caprylate, caprate, oleate, maleate, succinate, tartrate,citrate, glutamate, gluconate, esters or salts thereof, or combinationsthereof. In one aspect, the neutralizing agent is lactic acid.

In another embodiment, the matrix includes a hydrophilic internal phaseand a lipid or lipophilic external phase. The hydrophilic internal phasecan comprise polypropylene glycol or polyethylene glycol of molecularweight ranging from about 200 to about 8000 (M_(N), number averagemolecular weight). In another embodiment, the internal phase compriseshydroalcoholic solutions of cellulose derivatives, polyacrylates,polyvinyl polymers, or combinations thereof. In one embodiment, theinternal phase comprises polymers such as methylcellulose,hydroxypropylmethylcellulose, polymethylmethacrylate, orpolyvinylpyrrolidone (PVP). In one embodiment, the internal phase of thematrix state is “fluid” or “structured.” A “fluid” internal phase, asused herein, means a completely flowable liquid whose globules canaggregate to make a larger globule. A “structured” internal phase, asused herein, means a solid, semisolid, or a gel whose shape isrelatively stable and does not usually aggregate to form a largeglobule. A structured internal phase can provide controlled drug releaseand stabilize the physical state of the matrix. Without being bound toany theory, the structured nature of the matrix impedes solvation ordiffusion of the fumarate ester out of the matrix. In anotherembodiment, the external phase comprises a vegetable oil, hydrogenatedvegetable oil, fatty acid, fatty acid ester, wax, or a combinationthereof. In another embodiment, fumarate ester is dispersed in theinternal phase as a suspension form.

In another embodiment, the matrix fill is an emulsion type, where thefumarate ester is distributed in one or both of the external(lipophilic) and internal (hydrophilic) phases. The external phase ofthe emulsion matrix fill comprises lipid or lipophilic vehicles similarto those described herein. The fumarate ester can be dispersed in theinternal phase as a solution or as a suspension. For example, oneportion of the fumarate ester in the form of a powder is incorporated inthe internal phase, while another portion is dispersed in the externalphase as solid particles. An emulsion-type matrix may comprise asurfactant or combination of surfactants having HLB values ranging fromabout 2 to about 40, including all integers within the specified range.In one aspect, the HLB range comprises from about 8 to about 20,including all integers within the specified range.

In one embodiment, the pharmaceutical composition described hereincomprises a soft capsule comprising a matrix comprising a lipid orlipophilic vehicle that provides a solution, suspension, or combinationthereof of a fumarate ester. In one embodiment described herein, thefumarate ester is a mono- or di-alkyl fumarate of Formula I:

wherein R₁ and R₂, which may be the same or different, independentlyrepresent hydrogen or a linear, branched, or cyclic, saturated orunsaturated C₁₋₂₀ alkyl radical, which may be optionally substitutedwith halogen (Cl, F, I, Br), hydroxy, C₁₋₄ alkoxy, nitro, or cyano forpreparing a pharmaceutical composition as described herein.

The C₁₋₂₀ alkyl radicals, C₁₋₈ alkyl radicals, and C₄₋₅ alkyl radicalsare, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethyl hexyl, hexyl,cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxyethyl, 2or 3-hydroxy propyl, 2-methoxy ethyl, methoxy methyl or 2- or 3-methoxypropyl. In one aspect, at least one of R₁ or R₂ is a C₁₋₅ alkyl,especially methyl or ethyl. In another aspect, R₁ and R₂ are the same ordifferent C₁₋₅ alkyl radicals such as methyl, ethyl, n-propyl, ort-butyl. In one aspect, R₁ and R₂ are the same or different C₁₋₅ alkylradicals such as methyl and ethyl. In one aspect, R₁ and R₂ areidentical and are methyl or ethyl. In one aspect, the fumarate ester ismonomethyl fumarate, dimethyl fumarate, methyl ethyl fumarate, ordiethyl fumarate. In one aspect, the fumarate ester is monomethylfumarate, dimethyl fumarate, or a combination thereof. In one aspect,the fumarate ester is monomethyl fumarate. In another aspect, thefumarate ester is dimethyl fumarate.

In one embodiment, the fumarate ester is:

In one embodiment, the fumarate ester is:

In one embodiment, the fumarate ester is:

wherein R comprises any C₁₋₂₀ alkyl, any C₁₋₂₀ acid, any C₁₋₂₀ ether,any C₁₋₂₀ ester, any C₁₋₂₀ amino, any C₁₋₂₀ amide, or any C₁₋₂₀heterocycle.

In another embodiment described herein, the fumarate ester is a prodrugof monomethyl fumarate. In one aspect the monomethyl fumarate prodrug isdimethyl fumarate. Exemplary monomethyl fumarate prodrugs are describedin U.S. Pat. Nos. 8,669,281 and 9,090,558 and U.S. Patent ApplicationPublication Nos. US 2014/0275048; US 2014/0275205; US 2014/0275250; US2015/0190360; US 2014/057918; US 2014/348914; US 2014/350018; US2014/056973; US 2014/0348915; and US 2015/0252013, each of which isincorporated by reference herein for such teachings. In one embodiment,the prodrug comprises one or more of N,N-diethylcarbamoyl)methylmethyl(2E)but-2-ene-1,4-dioate; methyl [N-benzylcarbamoyl]methyl(2E)but-2-ene-1,4-dioate; methyl 2-morpholin-4-yl-2-oxoethyl(2E)but-2-ene-1,4-dioate; (N-butylcarbamoyl)methylmethyl(2E)but-2-ene-1,4-dioate; [N-(2-methoxyethyl)carbamoyl]methylmethyl(2E)but-2-ene-1,4-dioate;methyl(N-(1,3,4-thiadiazol-2yl)carbamoyl)methyl(2E)but-2ene-1,4-dioate;(N,N-dimethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;(N-methoxy-N-methylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate;bis-(2-methoxyethylamino)carbamoyl]methylmethyl(2E)but-2-ene-1,4-dioate; [N-(methoxycarbonyl)carbamoyl]methylmethyl(2E)but-2ene-1,4-dioate; methyl 2-oxo-2-piperazinylethyl(2E)but-2-ene-1,4-dioate; methyl 2-oxo-2-(2-oxo(1,3-oxazolidin-3yl)ethyl(2E)but-2ene-1,4-dioate; {N-[2-(dimethylamino)ethyl]carbamoyl}methylmethyl(2E)but-2ene-1,4-dioate; ethoxycarbonyloxyethyl methyl(2E)but-2-ene-1,4-dioate; methyl (methylethoxycarbonyloxy)ethyl(2E)but-2-ene-1,4-dioate; (cyclohexyloxycarbonyloxy)ethyl methyl(2E)but-2-ene-1,4-dioate; methyl (2-methyl propanoyloxy)ethyl(2E)but-2-ene-1,4-dioate; methyl phenylcarbonyloxyethyl(2E)but-2-ene-1,4-dioate; cyclohexylcarbonyloxybutyl methyl(2E)but-2-ene-1,4-dioate; [(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]ethylmethyl (2E)but-2-ene-1,4-dioate; methyl2-methyl-1-phenylcarbonyloxypropyl (2E)but-2-ene-1,4-dioate;(cyclohexyloxycarbonyloxy)ethyl methyl (2E)but-2-ene-1,4-dioate;3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-aminopropanoicacid;3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-2-aminopropanoicacid;3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-(2-aminoacetylamino)propanoicacid;3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-2-aminopropanoicacid;3-{[(2E)-3-(methoxycarbonyl)prop-2enoyloxy]ethoxycarbonyloxy}(2S)-2-aminopropanoicacid; methyl (2-morpholinoethyl)fumarate; methyl(3-morpholinopropyl)fumarate; methyl (4-morpholinobutyl)fumarate; methyl(5-morpholinopentyl)fumarate; methyl (6-morpholinohexyl)fumarate;(E)-2,2′-((2-((4-methoxy-4-oxobut-2-enoyl)oxy)ethyl)azanediyl)diaceticacid; methyl (2-(methyl(2-(methylsulfonyl)ethyl)amino)ethyl)fumarate;2-(dimethylamino)propyl methyl fumarate;(E)-2-((4-methoxy-4-oxobut-2-enoyl)oxy)-N,N,N-trimethylethanaminium;2-(4,4-difluoropiperidin-1-yl)ethyl methyl fumarate;1-(dimethylamino)propan-2-yl methyl fumarate; methyl(2-thiomorpholinoethyl)fumarate; methyl (2-(phenylamino)ethyl)fumarate;2-(dimethylamino)-2-methylpropyl methyl fumarate; methyl(2-(methylsulfonyl)ethyl)fumarate; 2-(1,1-dioxidothiomorpholino)ethylmethyl fumarate; 2-(benzyl(methyl)amino)ethyl methyl fumarate;2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate; methyl(2-(piperidin-1-yl)ethyl)fumarate; methyl (2-morpholinoethyl)fumarate;2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl methyl fumarate; methyl(2-(pyrrolidin-1-yl)ethyl)fumarate; 2-(dimethylamino)ethyl methylfumarate; 2-(diethylamino)ethyl methyl fumarate; or2-(diethylamino)-2-oxoethyl methyl fumarate, or pharmaceuticallyacceptable salts thereof. In one embodiment, the prodrug is(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, or a saltthereof. In another embodiment, the prodrug is2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate, or a salt thereof.

In one embodiment, the pharmaceutical compositions described hereincomprise pharmaceutically acceptable salts of the fumarate ester activepharmaceutical ingredient. The term “pharmaceutically acceptable salts”of an active ingredient includes alkali metal salts such as, sodium orpotassium salts, alkaline earth metal salts such as, for example,calcium and magnesium salts, and salts with organic or inorganic acidsuch as, for example, hydrochloric acid, hydrobromic acid, nitric acid,sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid,succinic acid, tartaric acid, methanesulphonic acid, toluenesulphonicacid, inter alia. In another embodiment, the active ingredient may alsobe in the form of pharmaceutically acceptable uncharged or chargedmolecules, molecular complexes, solvates, or anhydrates thereof, and, ifrelevant, single isomers, enantiomers, racemic mixtures, or mixturesthereof. In another embodiment, the active pharmaceutical ingredient maybe in any of its crystalline, polymorphous, semi-crystalline, amorphousor polyamorphous forms, or mixtures thereof.

The fumarate esters described herein can be prepared by processes knownin the art. See, e.g., EP 0 312 697 and U.S. Patent ApplicationPublication Nos. US 2013/0295169; US 2014/0179779; US 2014/0200363; andUS 2014/0364604, each of which is incorporated by reference herein forsuch teachings.

In one embodiment, the pharmaceutical composition comprises an activeingredient or drug. In one embodiment, the active ingredient or drug isa pharmacologically active fumarate ester. In one embodiment describedherein, the active ingredient is a monoalkyl fumarate. In one embodimentdescribed herein, the active ingredient is a dialkyl fumarate. In oneembodiment described herein, the active ingredient is a fumarate esteror combination of fumarate esters. In one embodiment described herein,the active ingredient is dimethyl fumarate. In another embodimentdescribed herein, the active ingredient is monomethyl fumarate (methylhydrogen fumarate). In another embodiment described herein, the activeingredient is a combination of dimethyl fumarate and monomethylfumarate. In another embodiment described herein, the active ingredientis a combination of dimethyl fumarate, monomethyl fumarate, and otherpharmacologically active fumarate esters, acids, salts, or derivativesthereof. In another embodiment, the active ingredient or drug comprisesdimethyl fumarate, monomethyl fumarate, other pharmacologically activefumarate esters, acids, or salts, derivatives thereof, or combinationsthereof. In another embodiment, the active ingredient comprises dimethylfumarate, monomethyl fumarate, or derivatives thereof, combined withaspirin, ibuprofen, naproxene, diclofenac, ketoprofen, celecoxib, othernon-steroidal anti-inflamatory active drugs (NSAIDs), or combinationsthereof. In one embodiment, the pharmaceutical composition comprises afumarate ester combined with aspirin.

In another embodiment, the pharmaceutical composition comprises afumarate ester combined with one or more leukotriene receptorantagonists. In another embodiment, the pharmaceutical compositioncomprises a fumarate ester combined with montelukast (Singulair®) orzafirlukast (Accolate®). In another embodiment, the pharmaceuticalcomposition comprises a fumarate ester combined with montelukast orzafirlukast and an NSAID. In another embodiment, the pharmaceuticalcomposition comprises a fumarate ester combined with montelukast orzafirlukast and aspirin.

In one embodiment, the fumarate ester-to-matrix fill ratio range (e.g.,the ratio of the fumarate ester weight to the weight of the othercomponents of the matrix fill or vehicle) comprises from about 1:50 toabout 1:1 by weight, including all ratios within the specified range. Inanother embodiment, the fumarate ester-to-matrix ratio range comprisesfrom about 1:10 to about 1:1 by weight, including all ratios within thespecified range. In one aspect, the fumarate ester-to-matrix ratiocomprises about 1:9 to about 1:1 by weight, including all ratios withinthe specified range. In another aspect, the fumarate ester-to-matrixratio range comprises from about 1:5 to about 1:1 by weight, includingall ratios within the specified range. In another aspect, the fumarateester-to-matrix ratio range comprises from about 1:3 to about 1:1.4 byweight, including all ratios within the specified range. In anotheraspect, the fumarate ester-to-matrix ratio is about 1:5; about 1:4;about 1:3; about 1:2; about 1:1; or about 0.5:1. In other aspects, thefumarate ester-to-matrix ratio is 1:3.5; 1:3.1; 1:2.9; 1:2.3; 1:2.5;1:1.92; 1:1.77; 1:1.5; 1:1.4; 1:1.35; 1:1.2, or about 1:1.2.

In one embodiment, the active ingredient comprises about 1% to about 70%of the matrix, including all integers and fractions within the specifiedrange. In another embodiment, the active ingredient comprises about 70%;about 60%; about 50%; about 40%; about 30%; about 20%; about 15%; about10%; about 5%; about 2%; or about 1% of the matrix fill. In one aspect,the active ingredient comprises about 64% of the matrix. In anotherembodiment, the active ingredient comprises about 57% of the matrix. Inanother embodiment, the active ingredient comprises about 50% of thematrix. In another embodiment, the active ingredient comprises about 34%of the matrix. In another embodiment, the active ingredient comprisesabout 32% of the matrix. In another embodiment, the active ingredientcomprises about 30% of the matrix. In another embodiment, the activeingredient comprises about 28% of the matrix. In another embodiment, theactive ingredient comprises about 25% of the matrix.

In one embodiment, the lipid or lipophilic liquid vehicle, includingsoluble components other than the fumarate ester, comprises about 50% toabout 88% of the matrix by weight, including all integers and fractionswithin the specified range. In one embodiment the lipid or lipophilicliquid vehicle comprise about 60% of the matrix by weight.

In one embodiment, the solid fumarate ester particles are milled ormicronized. In one embodiment, the fumarate ester comprises a particlesize range of about 1 μm to about 500 μm, including all integers andfractions within the specified range. In one aspect, the micronizedsolid fumarate ester particles have a particle size of about 1 μm, 2 μm,about 5 μm, about 10 μm, about 15 μm, about 20 μm, about 25 μm, about 30μm, about 35 μm, about 40 μm, about 45 μm, about 50 μm, about 55 μm,about 60 μm, about 65 μm, about 70 μm, about 75 μm, about 80 μm, about85 μm, about 90 μm, about 95 μm, about 100 μm, about 105 μm, about 110μm, about 115 μm, about 120 μm, about 125 μm, about 130 μm, about 135μm, about 140 μm, about 145 μm, about 150 μm, about 155 μm, about 160μm, about 165 μm, about 170 μm, about 175 μm, about 180 μm, about 185μm, about 190 μm, about 195 μm, about 200 μm, about 205 μm, about 210μm, about 215 μm, about 220 μm, about 225 μm, about 230 μm, about 235μm, about 240 μm, about 245 μm, about 250 μm, about 255 μm, about 260μm, about 265 μm, about 270 μm, about 275 μm, about 280 μm, about 285μm, about 290 μm, about 295 μm, about 300 μm, about 305 μm, about 310μm, about 315 μm, about 320 μm, about 325 μm, about 330 μm, about 335μm, about 340 μm, about 345 μm, about 350 μm, about 355 μm, about 360μm, about 365 μm, about 370 μm, about 375 μm, about 380 μm, about 385μm, about 390 μm, about 395 μm, about 400 μm, about 405 μm, about 410μm, about 415 μm, about 420 μm, about 425 μm, about 430 μm, about 435μm, about 440 μm, about 445 μm, about 450 μm, about 455 μm, about 460μm, about 465 μm, about 470 μm, about 475 μm, about 480 μm, about 485μm, about 490 μm, about 495 μm, about 500 μm, or even larger. In anotheraspect, the solid particles of fumarate ester comprise a distribution ofparticle sizes, comprising particles of any of the foregoing particlesizes.

In another embodiment, the solid fumarate ester particles have meanparticle size distributions (PSD) ranging from about 20 μm to about 300μm, including all integers and fractions within the specified range. Inone aspect, the solid particles of fumarate ester comprise mean particlesize distributions of about 20 μm, about 30 μm, about 40 μm, about 50μm, about 60 μm, about 70 μm, about 80 μm, about 90 μm, about 100 μm,about 120 μm, about 140 μm, about 160 μm, about 180 μm, about 190 μm,about 200 μm, about 220 μm, about 240 μm, about 260 μm, about 280 μm, orabout 300 μm. In one aspect, the solid particles of fumarate ester havea mean particle size distribution of about 260 μm. In one aspect, thesolid particles of fumarate ester have a mean particle size distributionof about 170 μm. In one aspect, the solid particles of fumarate esterhave a mean particle size distribution of about 140 μm. In one aspect,the solid particles of fumarate ester have a mean particle sizedistribution of about 100 μm. In one aspect, the solid particles offumarate ester have a mean particle size distribution of about 90 μm. Inone aspect, the solid particles of fumarate ester have a mean particlesize distribution of about 80 μm. In one aspect, the solid particles offumarate ester have a mean particle size distribution of about 25 μm.

In another embodiment, the solid fumarate ester particles have aparticle size distribution with a d90 of less than or equal to about 500μm. In one aspect, the particle size distribution of solid particles offumarate ester have a d90 of ≤ to about 20 μm, about 30 μm, about 40 μm,about 50 μm, about 60 μm, about 70 μm, about 80 μm, about 90 μm, about100 μm, about 120 μm, about 140 μm, about 160 μm, about 180 μm, about190 μm, about 200 μm, about 220 μm, about 240 μm, about 260 μm, about280 μm, about 300 μm, or about 400 μm. In one aspect, the solidparticles of fumarate ester have a particle size distribution with a d90of ≤ about 260 μm (d90≤260 μm). In one aspect, the solid particles offumarate ester have a particle size distribution with a d90 of about 170μm (d90≤170 μm). In one aspect, the solid particles of fumarate esterhave a particle size distribution with a d90 of ≤ about 140 μm (d90≤140μm). In one aspect, the solid particles of fumarate ester have aparticle size distribution with a d90 of ≤ about 100 μm (d90≤100 μm). Inone aspect, the solid particles of fumarate ester have a particle sizedistribution with a d90 of ≤ about 90 μm (d90≤90 μm). In one aspect, thesolid particles of fumarate ester have a particle size distribution witha d90 of ≤ about 80 μm (d90≤80 μm). In one aspect, the solid particlesof fumarate ester have a particle size distribution with a d90 of ≤about 25 μm (d90≤25 μm).

In another embodiment, the solid fumarate ester particles have a meanparticle size distribution comprising a range of particle sizes with ad10 of ≤10 μm and a d90 of ≤500 μm. In one aspect, the solid particlesof fumarate ester have a particle size distribution with a d10 of ≤ toabout 10 μm and a d90 of ≤ to about 400 μm, a d10 of ≤ to about 10 μmand a d90 of ≤ to about 300 μm, a d10 of ≤ to about 10 μm and a d90 of ≤to about 250 μm, a d10 of ≤ to about 10 μm and a d90 of ≤ to about 200μm, a d10 of ≤ to about 10 μm and a d90 of ≤ to about 150 μm, a d10 of ≤to about 10 μm and a d90 of ≤ to about 100 μm. In one aspect, the solidparticles of fumarate ester have a particle size distribution with a d10of ≤ to about 10 μm and a d90 of ≤ to about 100 μm, a d10 of ≤ to about20 μm and a d90 of ≤ to about 100 μm, a d10 of ≤ to about 30 μm and ad90 of ≤ to about 100 μm, a d10 of ≤ to about 40 μm and a d90 of ≤ toabout 100 μm, a d10 of ≤ to about 50 μm and a d90 of ≤ to about 100 μm,a d10 of ≤ to about 60 μm and a d90 of ≤ to about 100 μm, a d10 of ≤ toabout 70 μm and a d90 of ≤ to about 100 μm, a d10 of ≤ to about 80 μmand a d90 of ≤ to about 100 μm.

In another embodiment, the solid particles of fumarate ester comprisemultiple distributions of particle sizes. In one aspect, the solidparticles of fumarate ester may comprise a plurality of independentlycombined mean particle size distributions, wherein each independent meanparticle size distribution ranges from about 20 μm to about 300 μm,including all integers and fractions within the specified range. Inanother aspect, the plurality of mean particle size distributions cancomprise a mean particle size distribution of about 261 μm, a meanparticle size distribution of about 168 μm, a mean particle sizedistribution of about 148 μm, a mean particle size distribution of about100 μm, a mean particle size distribution of about 90 μm, a meanparticle size distribution of about 80 μm, or a mean particle sizedistribution of about 26 μm. In another aspect, the plurality of meanparticle size distributions can comprise combinations of independentmean particle size distributions, wherein each independently combinedmean particle size distribution is about 261 μm, about 168 μm, about 148μm, about 100 μm; about 90 μm, about 80 μm, or about 26 μm. In anotheraspect, the solid particles of fumarate ester comprise a combination ofindependently combined mean particle size distributions of about 30 μmto about 260 μm in a single matrix fill. Any of the foregoing particlesize distributions may be combined to provide the desired controlledrelease profile.

The forgoing sizes of fumarate ester particles may be determined usingstandard techniques known to one of ordinary skill in the art. Theexemplary techniques that can be used for measuring the size of fumarateester particles may include laser diffraction analysis, light scattering(e.g., dynamic light scattering), microscopic particle image analysis,elutriation, or aerosol mass spectrometry. The sample of fumarate esterparticles may be measured as a dry sample or a wet sample. Anycommercially available instrument for measuring particle sizes may beused, including instruments from Cilas; Brookhaven InstrumentsCorporation; Malvern Instruments; Horiba Scientific; or Wyatt followingthe recommended operating procedures according to the manufacturer'sinstructions.

The measured particle sizes using the techniques described herein may beexpressed as a derived diameter with a normal distribution or non-normaldistribution with a mean, median (e.g., mass median diameter), and modeof particle diameter sizes. The particle size distribution may beexpressed as a diameter number distribution, a surface areadistribution, or a particle volume distribution. The mean of theparticle size distribution may be calculated and expressed in variousways, such as the volume mean diameter (D[4,3] or d₄₃), mean surfacearea diameter (D[3,2] or d32) or the mean number particle diameter(D[1,0] or d₁₀). Because the particle size distribution values varydepending on the measurement methodology and how the distribution isexpressed, the comparison of different mean particle size distributionsmust be calculated by the same methodology in order to yield an accuratecomparison. For example, a sample with a measured and calculated volumemean diameter must be compared with a second sample having a measuredand calculated volume mean diameter, ideally measured using the samemeasuring instrument under the same conditions. Thus, the specificparticle size distributions described herein are not intended to belimited to any one type of method for measuring or calculating aparticle size distribution (e.g., a diameter number distribution, asurface area distribution, or a particle volume distribution), butrather indicate particle size values and distributions thereof for eachmethod of measuring particle sizes described herein.

Another embodiment described herein is a method for manufacturing a fillfor a controlled release pharmaceutical composition comprising particlesof fumarate esters such as dimethyl fumarate, monomethyl fumarate, orcombinations thereof of defined sizes. In one aspect, the particles areof a similar size distribution. In another aspect, the fumarate esterparticles comprise varied size distributions. In another aspect, thefumarate ester particles comprise several size distributions. In anotheraspect, the fumarate ester particles comprise a mixture of smaller andlarger size distributions. Without being bound to any theory, smallerparticles are generally solubilized and released more rapidly thanlarger particles. The release rate can be adjusted to achieve a specifictherapeutic window over a defined period and produce controlled release,delayed release, or extended release compositions by combining multiplefumarate ester particle sizes or size distributions.

Another embodiment described herein is a method for manufacturing apharmaceutical composition comprising fumarate ester(s) where thefumarate ester does not sublime during processing, manufacturing, afterproduction, or during storage. Soft capsules comprising fumarate esterin the matrix fills described herein are stable for months or years.Without being bound to any theory, it is believed that suspending solidfumarate ester in a lipid or lipophilic vehicle prevents or retardssublimation and stabilizes the fumarate ester. In one aspect, thepharmaceutical compositions described herein are stable at 25° C. and60% relative humidity (RH) for about 1 month, about 2 months, about 3months, about 4 months, about 5 months, about 6 months, about 9 months,about 10 months, about 11 months, about 12 months, about 18 months,about 24 months, or even longer. In another aspect, the pharmaceuticalcompositions described herein are stable for at least 1 year, or longerat 25° C. and 60% RH. In another aspect, the pharmaceutical compositionsdescribed herein are stable for at least 2 years, or longer at 25° C.and 60% RH.

Another embodiment described herein is a method for preparing apharmaceutical matrix comprising a fumarate ester. An exemplary schemeof a manufacturing process is shown in FIG. 1. The method comprisesapplying heat to the matrix components during mixing or prior to mixingat about the melting point of the matrix fill composition; and thenmixing the fumarate ester with the lipid or lipophilic matrixingredients using mechanical or ultrasonic forces to form the matrixfill. The matrix fill is flowable such that it can be encapsulated usinga rotary die encapsulation machine. In one embodiment, the matrixcomponents are heated to a temperature in the range of from about 25° C.to about 70° C. In another embodiment, the matrix components are heatedto a temperature in the range of from about 25° C. to about 30° C.

In one embodiment, the matrix comprises a lipid or lipophilic vehicle,solid particles of one or more fumarate esters, an optional neutralizingagent, and optional pharmaceutically acceptable excipients. In anotheraspect, the matrix comprises oils, polyvinylpyrrolidones, andsurfactants. In one aspect, the surfactant comprises polysorbate 80 orpolyoxyl 40 hydrogenated castor oil. In another aspect, the matrixcomprises, a mixture of mono- and di-glycerides, polyvinylpyrrolidone,polyoxyl 40 hydrogenated castor oil, and solid particles of one or morefumarate esters. In another aspect, the matrix comprises one or moreoils, and solid particles of one or more fumarate esters. In anotheraspect, the solid particles of one or more fumarate esters are solublein the matrix fill.

In one embodiment, the matrix comprises the composition shown in Table 1including all possible iterations of the specified ranges that provide100% total weight percentage.

TABLE 1 Exemplary Matrix Fill Composition Ingredient mg/capsule % weightFumarate Ester (PSD: d90 ≤ 100 μm) 200-215 32-35 Lipid or lipophilicvehicle 370-425 60-70 Excipients  0-50 0-8 TOTAL 625 mg 100%

In one embodiment, the matrix comprises about 29% by weight of fumarateester (PSD: d90≤100 μm); about 50% by weight of a mixture of mono- anddi-glycerides; at least about 1-15% by weight of polyvinylpyrrolidone;at least about 2-10% by weight of polyoxyl 40 hydrogenated castor oil,and at least about 0-5% by weight of lactic acid, including alliterations of the specified ranges. In one aspect, the compositionprevents sublimation of the FAE during processing and manufacturing. Inone aspect, the composition reduces the onset of symptoms ofgastrointestinal side effects. In another aspect, the composition isstable for at least 6 months at 25° C. and 60% relative humidity. In oneaspect, the composition is stable for at least 24 months.

In one embodiment, the composition comprises one of those shown in Table2 including all possible iterations of the specified ranges that provide100% total weight percentage.

TABLE 2 Exemplary Matrix Fill Compositions Ingredient mg/capsule %weight Fumarate ester PSD: d90 ≤ 100 μm 200-215 32-35 Mono- anddi-glycerides 125-315 20-50 Polyvinyl pyrrolidone  5-32 0.75-5  Polyoxyl 40 Hydrogenated castor oil 12.5-75   2-12 Lactic acid  0-32 0-5TOTAL 625 100% Fumarate ester PSD: d90 ≤ 100 μm 200-215 32-35 Soybeanoil 410-425 65-70 TOTAL 625 100%

In another embodiment, the matrix fill comprises about 32% to 35% offumarate ester (PSD: d90≤100 μm); about 20% to about 50% of a mixture ofmono- and di-glycerides; at least about 0.75-5% polyvinylpyrrolidone; atleast about 2-12% polyoxyl 40 hydrogenated castor oil; and at leastabout 0-5% lactic acid, including each integer within each of thespecified ranges. In one embodiment, the lactic acid is optional. Inanother embodiment, the matrix fill comprises about 32% to 35% offumarate ester (PSD: d90≤100 μm) and about 65% to about 70% of soybeanoil, including each integer within each of the specified ranges. Inanother embodiment, the lactic acid is optionally added to the soybeanoil matrix. In one aspect, the composition prevents sublimation of theFAE during processing and manufacturing. In another aspect, thecomposition reduces the onset of symptoms of any gastrointestinal sideeffects. In another aspect, the composition is stable for at least 6months at 25° C. and 60% relative humidity. In another aspect, thecomposition is stable for at least 24 months at 25° C. and 60% relativehumidity. In another aspect, the composition is liquid at roomtemperature.

In one embodiment, the fumarate ester pharmaceutical compositioncomprises a capsule dosage form. In one embodiment, the fumarate esterpharmaceutical composition comprises a soft capsule encapsulating amatrix fill comprising a liquid lipid or lipophilic fill comprising oneor more fumarate esters.

In one embodiment described herein, the soft capsule shell has thecomposition of Table 3, including all possible iterations of thespecified ranges that provide 100% for the total weight percentage,including or excluding optional colorings, opacifiers, flavorings, orother excipients.

TABLE 3 Exemplary Soft Gelatin Capsule Composition Component ExemplaryComponent Weight Percentage (%) Film-forming polymer Gelatin, 150-20020-48 Bloom Plasticizer Glycerol, sorbitol 10-30 Solvent Water 20-70Opacifier (optional) Titanium dioxide  0-1.5 Coloring agent (optional)Various  0-0.1 Excipients (optional) Various 0-5 TOTAL 100%

Film-former polymers that are useful for creating soft capsules aregelatin, hydroxypropylmethylcellulose (HPMC) or carrageenan (e.g., iotacarrageenan and kappa carrageenan). In one embodiment described herein,the film-forming polymer is gelatin.

Examples of gelatin compositions that are useful for creating softcapsule shells as described herein comprise acid bone gelatin, pig skingelatin, chicken skin gelatin, fish gelatin, acid hide gelatin, gelatinhydrolysate, lime bone gelatin, or combinations thereof. Gelatins thatare useful for creating soft capsules described herein can be classifiedas either Type A or Type B gelatin. Type A gelatin is derived from theacid hydrolysis of collagen (e.g., acid bone gelatin or pig skingelatin), while Type B gelatin (e.g., lime bone gelatin) is derived fromthe alkaline hydrolysis of collagen. Traditionally, bovine bones andskins are used as raw materials for manufacturing Type A and Type Bgelatin, while porcine skins are used extensively for manufacturing TypeA gelatin. In addition, at neutral pH values, Type A gelatins (acidprocessed gelatins) are typically net cationic (e.g., isoelectric pointof about 7-9) and Type B gelatins (alkali processed gelatins) aretypically net anionic (e.g., isoelectric point of about 4.5-5.3). Type Agelatin typically has higher plasticity and elasticity than type Bgelatin; type B gelatin typically has higher gel strength than type Agelatin.

The strength of gelatin compositions is typically defined by their Bloomstrength or grade. The Bloom test determines the weight (in grams)needed by a 0.5-inch diameter probe to deflect the surface of a gel 4 mmwithout breaking it. The result is expressed as “Bloom” or “Bloomstrength.” The soft capsules described herein utilize gelatins withBloom strengths in the range of about 20 Bloom to about 400 Bloom,including each integer within the specified range. In one embodiment,Bloom strengths for soft capsules described herein are about 50 Bloom toabout 250 Bloom including each integer within the specified range. Insome embodiments, the gelatin Bloom strength is about 50 Bloom, about 80Bloom, about 100 Bloom, about 120 Bloom, about 150 Bloom, about 180Bloom, about 200 Bloom, or about 250 Bloom. In one embodiment, thegelatin Bloom strength is 100 Bloom. In another embodiment, the gelatinBloom strength is 150 Bloom. In another embodiment, the gelatin Bloomstrength is 195 Bloom. In another embodiment, the gelatin Bloom strengthis 200 Bloom.

Plasticizers that are useful for creating soft capsules as describedherein are glycerol, sorbitol, partially dehydrated sorbitol (a blend ofD-sorbitol, 1,4-sorbitan, mannitol, and water; e.g., Sorbitol Special®(SPI Pharma); Anidrisorb® or Polysorb®, (Roquette)), maltitol(hydrogenated corn syrup; e.g., Lycasin®, Roquette), corn syrup,xylitol, mannitol, propylene glycol, low molecular weight polyethyleneglycols, poly-alcohols with 3 to 6 carbon atoms, or a combinationthereof. Plasticizers typically comprise about 10-30% of the total wetmass of a shell, including each integer within the specified range. Theweight ratio between the film-forming polymer, plasticizer, and solventis adjusted so that the gel mass is flowable and not too viscous, andcan be made into soft capsules using rotary die encapsulation methods.

In one embodiment described herein, the soft capsule shell has theexemplary composition shown in Table 4.

TABLE 4 Exemplary Soft Capsule Shell Composition Component Percentweight (%) Film forming polymer (e.g., gelatin) 20-50 Plasticizer (e.g.,glycerol, sorbitol, 15-30 combinations thereof) Solvent (e.g., water)q.s. (e.g., 20-40%) TOTAL 100% Final pH ~4-7  Ratio total plasticizer togelatin 20:43 (0.46:1) Water content in dried soft capsule shell: 8-15% 

In one embodiment, the weight percentage range of film-forming polymerof the soft capsule described herein is about 20% to about 50%,including all integers within the specified range. In one aspect, thefilm-forming polymer weight percentage is about 38%. In another aspect,the film-forming I polymer weight percentage is about 42%. In anotheraspect, the film-forming polymer weight percentage is about 44%.

In one embodiment, the weight percentage range of plasticizer is about15% to about 30%, including all iterations of integers with thespecified range. In one aspect, the plasticizer weight percentage isabout 24%. In another aspect, the plasticizer weight percentage is about22%. In another aspect, the plasticizer weight percentage is about 20%.

In one embodiment, the solvent comprises about 20% to about 40% of thesoft capsule composition, including all integers and fractions withinthe specified range. In one embodiment, the solvent is water. Thequantity of water in the composition varies depending on the quantitiesof the other ingredients. For example, the quantity of plasticizer,opacifier, colorant, flavoring, or other excipients can change thepercentage of water present in the composition. In one embodiment, theweight percentage of water is as much as suffices to bring the totalweight percentage to 100% (i.e., quantum sufficiat; q.s.). In anotherembodiment, the water comprises about 20%, about 25%, about 30%, about35%, or about 40% of the enteric soft capsule composition. In anotherembodiment, water comprises about 30% to about 40% of the enteric softcapsule composition. In one embodiment, water comprises about 34% of thecomposition.

In one embodiment, the final moisture (water) content of the softcapsule after manufacturing and drying is from about 8% to about 15%,including all integers and fractions within the specified range. Inanother embodiment, the moisture content is about 8% to about 12%,including all integers and fractions within the specified range. In oneaspect, the final moisture content is about 12%. In one aspect, thefinal moisture content is about 11%. In one aspect, the final moisturecontent is about 10%. In one aspect, the final moisture content is about9%. In another aspect, the final moisture content is about 8%.

In one embodiment, the weight percentage ratio range of plasticizer tofilm-forming polymer is about 0.33:1 to about 0.56:1, including alliterations of iterations of ratios with the specified range. In oneembodiment, the weight percentage ratio range of plasticizer tofilm-forming polymer is about 0.38:1. In one embodiment, the weightpercentage ratio range of plasticizer to film-forming polymer is about0.42:1. In one embodiment, the weight percentage ratio range ofplasticizer to film-forming polymer is about 0.46:1. In one embodiment,the weight percentage ratio range of plasticizer to film-forming polymeris about 0.52:1.

In one embodiment described herein, the soft capsule comprises about 42%of at least one film-forming polymer; about 24% of at least oneplasticizer; and about 34% water.

In another embodiment, the soft capsule shell has the exemplarycomposition shown in Table 5.

TABLE 5 Exemplary Soft Capsule Shell Composition Component Percentweight (%) Gelatin, 150 Bloom, Lime Bone 42 Sorbitol (e.g., Polysorb ®85/70/00; Roquette) 24 Water 34 TOTAL 100%

In another embodiment, the soft gel capsule shell has the exemplarycomposition shown in Table 6.

TABLE 6 Exemplary Soft Gel Capsule Shell Composition Component Percentweight (%) Gelatin, 195 Bloom, Lime Bone 42 Sorbitol (e.g., Polysorb ®85/70/00; Roquette) 24 Water 34 TOTAL 100%

In one aspect, soft capsules are made using a rotary die apparatus asdescribed in U.S. Pat. Nos. 5,459,983; 5,146,730; and 6,482,516, each ofwhich are incorporated by reference herein for such teachings.

Another embodiment described herein includes a process of manufacturingsoft capsules comprising any of the pharmaceutical composition asdescribed herein. The process includes preparing a gel mass compositioncomprising a film-forming, water-soluble polymer, an appropriateplasticizer, and solvent; casting the gel mass into films or ribbonsusing heat-controlled drums or surfaces; and manufacturing a softcapsule comprising a matrix fill using rotary die technology. Thethickness of the films or ribbons that form the soft capsule shell isfrom about 0.010 inches (≈0.254 mm) to about 0.050 inches (≈1.27 mm),including all integers within the specified range. The shell thicknesscan be about 0.010 inch (≈0.254 mm), about 0.015 inch (≈0.381 mm), about0.02 in (≈0.508 mm), about 0.03 in (≈0.762 mm), about 0.04 in (≈1.02mm), or about 0.05 in (≈1.27 mm). In one embodiment, the thickness isabout 0.02 inches (≈0.508 mm) to about 0.040 inches (≈1.02 mm). In oneembodiment, the shell thickness is about 0.028 inches (≈0.711 mm). Inanother embodiment, the shell thickness is about 0.033 inches (≈0.838mm). In another embodiment, the shell thickness is about 0.038 inches(≈0.965 mm). In another embodiment, the shell thickness is about 0.035inches (≈0.889 mm). In another embodiment, the shell thickness is about0.038 inches (≈0.965 mm). In another embodiment, the shell thickness isabout 0.040 inches (≈1.02 mm).

In one embodiment described herein, the soft capsule shell describedherein, encapsulates a matrix fill as described herein. In anotherembodiment described herein, the soft capsule shell and encapsulatedmatrix fill comprises an outer dimension from about 2 oval to about 30oval including all iterations of capsule size within the specified range(e.g., 2 oval, 3 oval, 4 oval, 5 oval, 6 oval, 7 oval, 8 oval, 10 oval,12 oval, 16 oval, 20, or 30 oval). In another embodiment describedherein, the soft capsule shell and encapsulated matrix fill comprises anouter dimension from about 2 round to about 28 round including alliterations of capsule size within the specified range (e.g., 2 round, 3round, 4 round, 5 round, 6 round, 7 round, 8 round, 10 round, 12 round,16 round, 20 round or 28 round). In another embodiment described herein,the soft capsule shell and encapsulated matrix fill comprises an outerdimension from about 2 oblong to about 22 oblong including alliterations of capsule size within the specified range (e.g., 2 oblong, 3oblong, 4 oblong, 5 oblong, 6 oblong, 7 oblong, 8 oblong, 10 oblong, 11,oblong, 12 oblong, 14 oblong, 16 oblong, 20 oblong, or 22 oblong).Dimension specifications of soft capsules and tablets are known to thoseskilled in the art. See Remington's Essentials of Pharmaceutics,Pharmaceutical Press Publishing Company, London, UK, 1^(st) Edition,2013, which is incorporated by reference herein for such teachings.

In another embodiment, the fumarate ester pharmaceutical composition cancomprise an enteric soft capsule shell comprising a matrix comprising afumarate ester. Enteric soft capsules, e.g., soft capsules havingenteric polymers integrated into the capsule shell, are described inInternational Patent Application Publication No. WO 2004/030658; U.S.Patent Application Publication No. US 2006/0165778; and U.S. Pat. No.8,685,445, each of which is incorporated by reference herein for suchteachings. The enteric soft capsule shell may comprise one or more filmforming polymers, one or more enteric acid-insoluble polymers, one ormore plasticizers, one or more alkali-neutralizing agents, one or moresolvents, optionally one or more colorants, and optionally one or moreflavorings or other conventionally accepted pharmaceutical excipients oradditives.

Film-forming polymers that are useful for creating enteric soft capsulesare gelatin or hydroxypropylmethylcellulose (HPMC). In one aspect of theenteric soft capsule shell described herein, the film-forming polymer isgelatin.

Examples of enteric, acid-insoluble polymers are acrylic andmethacrylate acid copolymers, cellulose acetate phthalate (CAP),cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate(HPMCP), algenic acid salts such as sodium or potassium alginate, orshellac. Poly(methacylic acid-co-methyl methacrylate) anionic copolymersbased on methacrylic acid and methyl methacrylate are particularlystable and are preferred in some embodiments. Poly(meth)acrylates(methacrylic acid copolymer), available under the trade name EUDRAGIT®(Evonik Industries AG, Essen, Germany), are provided as powder oraqueous dispersions. In another aspect, the methacrylic acid copolymercomprises EUDRAGIT® L 30 D-55; EUDRAGIT® L 100-55; EUDRAGIT® L 100;EUDRAGIT® L 12.5; EUDRAGIT® S 100; EUDRAGIT® S 12.5; EUDRAGIT® FS 30 D;EUDRAGIT® E 100; EUDRAGIT® E 12.5; EUDRAGIT® E PO; EUDRAGIT® RL 100;EUDRAGIT® RL PO; EUDRAGIT® RL 30 D; EUDRAGIT® RL 12.5; EUDRAGIT® RS 100;EUDRAGIT® RS PO; EUDRAGIT® RS 30 D; EUDRAGIT® RS 12.5; EUDRAGIT® NE 30D; EUDRAGIT® NE 40 D; EUDRAGIT® NM 30 D; other poly(meth)acrylatepolymers; or a mixture thereof. In one aspect, the enteric polymer isEUDRAGIT® L 100, a methacrylic acid copolymer, Type A. Acid-insolublepolymer specifications are detailed in the United States Pharmacopoeiaand in various monographs.

In another embodiment described herein, the enteric polymer in theenteric soft capsule shell comprises poly(methacylic acid-co-ethylacrylate) 1:1 (e.g., EUDRAGIT® L 100-55). In one embodiment describedherein, the enteric polymer comprises poly(ethyl acrylate-co-methylmethacrylate) 2:1 (e.g., EUDRAGIT® NE 40 D). In another embodimentdescribed herein, the enteric polymer comprises poly(methylacrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 (e.g.,EUDRAGIT® FS 30 D). In another embodiment described herein, the entericpolymer comprises a combination of poly(methacylic acid-co-ethylacrylate) 1:1 and poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1. In another embodiment, theenteric polymer comprises a combination of poly(methacylic acid-co-ethylacrylate) 1:1 and poly(ethyl acrylate-co-methyl methacrylate) 2:1. Inanother embodiment, the enteric polymer comprises a combination ofpoly(methacylic acid-co-ethyl acrylate) 1:1, poly(ethylacrylate-co-methyl methacrylate) 2:1, and poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1.

In another embodiment, plasticizers that are useful for creating entericsoft capsules as described herein are glycerol, sorbitol, SorbitolSpecial®, maltitol, corn syrup, propylene glycol, poly-alcohols with 3to 6 carbon atoms, polyethylene glycol, citric acid, citric acid esters,such as tri-ethyl citrate, or combinations thereof. The weight ratiobetween the film-forming polymer, the enteric acid-insoluble polymer,and plasticizer is adjusted so that the gel mass is flowable and not tooviscous, and can be made into soft capsules using rotary dieencapsulation methods.

In one embodiment, enteric soft capsule shell compositions are made bydissolving the enteric acid-insoluble polymer in an aqueous solution ofan alkali-neutralizing agent such as ammonia, sodium hydroxide,potassium hydroxide, or liquid amines such as tri-ethanol amine orethylene diamine. The amount of alkali is adjusted to give a final pHvalue of the gel mass less than or equal to about pH 9.0. In oneembodiment, the final pH does not exceed 8.5. The volatilealkali-neutralizing agent, ammonia is preferred. The film-formingpolymer can then be combined with the plasticizer and solvent and thenblended with the acid-insoluble gel to make a final homogeneous mix in aheat-controlled vessel with degassing by vacuum. The fugitive ammoniaevaporates during degassing. Using the foregoing process, the alkaliconcentrations do not require heating or neutralizing with acid in orderto neutralize the gel mass.

In another embodiment described herein, the enteric soft capsule shellis made using an aqueous dispersion of the acid-insoluble polymer byadding an alkali-neutralizing agent such as ammonium, sodium, orpotassium hydroxides, other alkalis, or a combination thereof that willcause the enteric acid-insoluble polymer to dissolve. Theplasticizer-wetted, film-forming polymer can then be mixed with thesolution of the acid-insoluble polymer. In one embodiment, entericacid-insoluble polymers in the form of salts of the bases or alkalis asdescribed herein are dissolved directly in water and mixed with theplasticizer-wetted, film-forming polymer.

In one embodiment described herein, enteric acid-insoluble polymers inthe form of salts of the bases or alkalis described herein are dissolveddirectly in water and mixed with the plasticizer-wetted, film-formingpolymer. In another embodiment described herein, an aqueous dispersionof the acid-insoluble polymer or polymers is used, which obviates theneed for the addition of the alkali-neutralizing agent described herein.

In one embodiment, the enteric soft capsule shell has the composition ofTable 7, including all possible iterations of the specified ranges thatprovide 100% for the total weight percentage, including or excluding theoptional, excipients, opacifiers, colorants, and flavorings.

TABLE 7 Enteric Soft Capsule Shell Composition Exemplary CompositionComponent Component Range (%) Film-forming polymer Gelatin 20-36Enteric, acid-insoluble Methacrylic Acid  8-20 polymer CopolymerPlasticizer Glycerol, sorbitol, 15-22 Triethyl citrateAlkali-neutralizing NH₄OH (30%), 1-5 agents NaOH Solvent Water 20-40Opacifier (optional) Titanium Dioxide  0-7.5 Colorant (optional) Various0-1 Flavoring (optional) Various 0-2 Excipients (optional) Various 0-5

In one embodiment, the enteric soft capsule shell comprises acomposition of about 30% film forming polymer; about 10% enteric,acid-insoluble polymer; about 20% plasticizer; about 1%alkali-neutralizing agent; and about 37% solvent.

In another embodiment, the weight percentage range of total polymercontent (i.e., film forming polymer and enteric acid-insoluble polymer)of the enteric soft capsule described herein is about 30% to about 45%,including all integers and fractions within the specified range. In oneaspect, the total polymer weight percentage is about 40%. In anotheraspect, the total polymer weight percentage is about 42%. In anotheraspect, the total polymer weight percentage is about 45%. In anotheraspect, the total polymer weight percentage is about 38%.

In one embodiment, the weight percentage range of total plasticizer isabout 15% to about 22%, including all integers and fractions within thespecified range. In one aspect, the total plasticizer weight percentageis about 19%. In another aspect, the total plasticizer weight percentageis about 17.7%. In another aspect, the total plasticizer weightpercentage is about 18.9%. In another aspect, the total plasticizerweight percentage is about 19.3%.

In one embodiment, the alkali-neutralizing agent is ammonia (ammoniumhydroxide; 30% w/v) that is added to comprise a weight percentage ofabout 1% to about 5% of the total enteric soft capsule composition. Inone aspect, 30% w/v ammonia is added to comprise a weight percentage ofabout 2%. In another aspect, 30% w/v ammonia is added to comprise aweight percentage of about 1.7%. In one aspect, ammonia is added toprovide a final pH of about 9 in the enteric soft capsule composition.In another aspect, ammonia is added to provide a final pH of about 8.5in the enteric soft capsule composition. In another aspect, after thecapsules are filled and dried, the ammonia concentration issubstantially reduced, owing to the fugitive nature of the volatilealkali-neutralizing agent. In another aspect, practically all of theammonia is evaporated except for ammonium ions comprising salts withother moieties in the composition.

In one embodiment, the weight ratio range of film forming polymer toenteric acid-insoluble polymer (i.e., film forming: enteric) is about25:75 (≈0.33) to about 40:60 (≈0.67) (i.e., ≈0.33-0.67), including allratios within the specified range. In one aspect, the ratio of filmforming polymer to enteric acid-insoluble polymer is about 30:70(≈0.43). In another aspect, the ratio of film forming polymer to entericacid-insoluble polymer is about 28:72 (≈0.38).

In one embodiment, the weight ratio of total plasticizer to film formingpolymer is about 20:40 to 21:30 (i.e., ≈0.5-0.7), including all ratioswithin the specified range. In one aspect, the weight ratio of totalplasticizer to film forming polymer is about 20:40 (≈0.5). In anotheraspect, the weight ratio of total plasticizer to film forming polymer isabout 21:30 (≈0.7). In another aspect, the weight ratio of totalplasticizer to film forming polymer is about 19:29 (≈0.65). In anotheraspect, the weight ratio of total plasticizer to film forming polymer isabout 19.3:29.2 (≈0.66).

In one embodiment, the weight ratio of total plasticizer to entericacid-insoluble polymer is about 1:1 to about 2:1 (≈1-2), including allratios within the specified range. In one aspect, the weight ratio oftotal plasticizer to enteric acid-insoluble polymer is about 11:10(≈1.1). In another aspect, the weight ratio of total plasticizer toenteric acid-insoluble polymer is about 14:10 (≈1.4). In another aspect,the weight ratio of total plasticizer to enteric acid-insoluble polymeris about 17:10 (≈1.7). In another aspect, the weight ratio of totalplasticizer to enteric acid-insoluble polymer is about 20:10 (≈2). Inanother aspect, the weight ratio of total plasticizer to entericacid-insoluble polymer is about 19.3:11.2 (≈1.73).

In one embodiment, the weight ratio range of total plasticizer to totalpolymer (film forming and enteric acid-insoluble polymer) is about 18:45to about 20:40 (i.e., ≈0.40-0.5), including all ratios within thespecified range. In one aspect, the weight ratio range of totalplasticizer to total polymer is about 18:45 (≈0.40). In another aspect,the weight ratio range of total plasticizer to total polymer is about19:40 (≈0.475). In another aspect, the weight ratio range of totalplasticizer to total polymer is about 20:40 (≈0.5). In another aspect,the weight ratio range of total plasticizer to total polymer is about19.3:40.4 (≈0.477).

In one embodiment, the solvent comprises about 20% to about 40% of theenteric soft capsule composition, including all integers and fractionswithin the specified range. In one embodiment, the solvent is water. Thequantity of water in the composition varies depending on the quantitiesof the other ingredients. For example, the quantity of opacifier,colorant, flavoring, or other excipients can change the percentage ofwater present in the composition. In one embodiment, the weightpercentage of water is as much as suffices to bring the total weightpercentage to 100% (i.e., quantum sufficiat; q.s.). In anotherembodiment, the water comprises about 20%, about 25%, about 30%, about35%, or about 40% of the enteric soft capsule composition. In anotherembodiment, water comprises about 35% to about 40% of the enteric softcapsule composition. In one embodiment, water comprises about 37% of thecomposition.

In one embodiment, the final moisture (water) content of the entericsoft capsule is from about 8% to about 15%, including all integers andfractions within the specified range. In another embodiment, themoisture content is about 8% to about 12%, including all integers andfractions within the specified range. In one aspect, the final moisturecontent is about 8%. In one aspect, the final moisture content is about9%. In one aspect, the final moisture content is about 10%. In oneaspect, the final moisture content is about 11%. In another aspect, thefinal moisture content is about 12%.

In one embodiment, the enteric soft capsule shell has the exemplarycomposition shown in Table 8.

TABLE 8 Exemplary Enteric Soft Capsule Shell Composition ComponentPercent weight (%) Gelatin 29.2 Methacrylic Acid Copolymer (EUDRAGIT ®11.2 L 100) Glycerol or Sorbitol 18.0 Triethyl citrate 1.3 Ammoniumhydroxide 1.7 Titanium dioxide 1.5 Water 37.1 TOTAL  100% Final pH8.5-9.0 Total polymer % weight (gelatin + enteric) 40.4% Gelatin % wt oftotal polymer (gelatin + enteric) 72.4% Enteric % wt of total polymer(gelatin + enteric) 27.6% Ratio of Enteric to Gelatin 11.2:29.2 (0.38)Total plasticizer % weight (glycerol + triethyl 19.3% citrate) Ratio oftotal plasticizer to total polymer 19.3:40.4 (0.48) Ratio totalplasticizer to gelatin 19.3:29.2 (0.66) Ratio total plasticizer toenteric 19.3:11.2 (1.73) Water content in dried enteric soft capsule:8-15%

In one embodiment, the enteric soft capsule shell comprises about 30%gelatin; about 10% poly(methyl) acrylate copolymer; about 18% glycerol;about 1% triethyl citrate; about 1.5% ammonia; about 37% water; andabout 1.5% titanium dioxide.

In another embodiment, the enteric soft capsule is described in U.S.patent application Ser. No. 14/744,057, which is incorporated byreference herein for such teachings.

One embodiment described herein provides an enteric acid-insolublepolymer dispersed within the film-forming polymer gel mass that providesthe total soft gel composition with enteric acid-insoluble properties,at relatively low concentrations of the enteric acid-insoluble polymer(e.g., from about 8% to about 20% of the total wet gel mass composition)and without the need of excessive amounts of alkali, thus avoidingdenaturation or degradation of the film-forming polymer that can weakenthe integrity of the enteric soft capsule shell.

Films of the enteric soft capsule shell do not dissolve or disintegratein acids, such as 0.1 N hydrochloric acid or simulated gastric fluid(ca. pH 1.2), despite the fact that the majority of the shellingredients (i.e., greater than 50%) normally dissolve in, or aremiscible with, acids. Enteric soft capsules made using the compositionsdescribed herein remain intact in hydrochloric acid or simulated gastricfluid for at least two hours. The capsules readily release the contentsupon shifting the pH of the solution to ca. 6.8, such as that ofsimulated intestinal fluid.

In another embodiment, the final enteric capsule composition providesfilms of increased strength without substantially compromising filmelasticity. Moreover, films made from the enteric soft capsulecompositions as described herein are sealed at normal temperature rangetypically used for making traditional soft gel capsules. In one aspect,enteric soft capsules are made using a rotary die apparatus as describedherein.

Another embodiment described herein includes a process of manufacturingenteric soft capsules comprising the pharmaceutical composition asdescribed herein. The process includes preparing a gel mass compositioncomprising a film-forming, water-soluble polymer and an entericacid-insoluble polymer and mixing with appropriate plasticizers andsolvent; casting the gel mass into films or ribbons usingheat-controlled drums or surfaces; and manufacturing a soft capsulecomprising a matrix fill using rotary die technology. The thickness ofthe films that form the enteric capsule and the dimensions of thecapsules are similar to those described herein.

In one embodiment described herein, enteric soft capsules are“traditional” soft capsules coated with an enteric coating. In anotherembodiment described herein, enteric soft capsules are soft capsuleshaving enteric polymers embedded within the capsule shell (e.g., anenteric soft capsule) and are coated with an enteric coating. Withoutbeing bound to any theory, it is believed that enteric coatings, inaddition to providing acid-resistance or pH-dependently release, alsoprevent the influx of water or other solvents into soft capsules or softcapsules having enteric polymers imbedded in the shell wall thatsolubilize the fumarate ester and facilitate diffusion of the fumarateester out of the capsule. Experiments described herein demonstrate thatsoft capsules with enteric polymers embedded within the shell wallcontaining dimethyl fumarate do not substantially release the dimethylfumarate under acidic media. When monomethyl fumarate is substituted fordimethyl fumarate in similar capsules, however, monomethyl fumarate isreleased from enteric soft capsules in acidic media. FIG. 16-19. Withoutbeing bound to any theory, it is though that the increased solubility ofMMF contributes to the release of this molecule by facilitating solventinflux through the capsule shell and resulting in diffusion of themonomethyl fumarate out of the capsule. Enteric coatings on softcapsules or soft capsules comprising enteric polymers embedded withinthe capsule shell abrogate the influx of solvent and impede the relaseof the monomethyl fumarate active pharmaceutical ingredient. FIG. 20-23.

In one embodiment described herein, soft capsules are coated with anenteric coating comprising the exemplary composition shown in Table 9.

TABLE 9 Exemplary Enteric Coating Composition Component ExemplaryComponent Weight Percentage (%) Enteric Methacrylic acid copolymers,5-90 Polymer(s) polyvinyl acetate phthalates, polyvinyl phthalate,cellulose acetate phthalates, cellulose acetate trimellitate, celluloseacetate succinate, hydroxypropyl methylcellulose, carboxymethylcellulose Plasticizer(s) Triethyl citrate, tributyl citrate, 0-25polyethylene glycols, propylene glycol, triacetin, dibutyl phthalate,tripropionin, ethyl acid phtalate, butyl acid phthalate, ethyl acidadipate, fats and waxes mixed with esters, glycerin NeutralizingAmmonia, NaOH, sodium 0-5  agent bicarbonate Solubilizers Sodium laurylsulfate, sodium lauroyl sarcosinate sodium dodecyl sulfate, polysorbate20, polysorbate 80, other detergents and surfactants Solvent(s) Water,ethanol, isopropanol, 50-80  acetone Excipients Emulsifiers,pore-forming 0-20 agents, anti-adherents, surfactants, pigments,colorants, antifoam, antioxidants, waxes, magnesium stearate, micronizedamorphous silica, kaolin, talc,

Enteric polymers useful for enteric coatings include pH-dependentpolymers that are less soluble in an aqueous media with acidic pH andmore soluble in an aqueous media with basic pH. In one embodiment, theenteric of pH dependent material dissolves or rapidly disperses at a pHlevel above pH 5.0, above pH 5.5, or above pH 6.0.

Exemplary enteric polymers useful for coats include cellulose acetatephthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate,cellulose acetate trimellitate, carboxymethylcellulose, methacrylic acidcopolymers such as, Eudragit L (polymethacrylic acid,methylmethacrylate, 1:1 ratio), or Eudragit S (polymethacrylic acid,methylmethacrylate, 1:2 ratio), shellac, zein, or combinations thereof.

Suitable plasticizers include acetyl triethyl citrate, dibutylphthalate, tributyl citrate, triethyl citrate, acetyl tributyl citrate,propylene glycol, triacetin, polyethylene glycol, diethyl phthalate, orcombinations thereof.

Suitable solubilizers include sodium lauryl sulfate, sodium lauroylsarcosinate sodium dodecyl sulfate, polysorbate 20, polysorbate 80,other detergents or surfactants, or combinations thereof.

Anti-adherent agents serve to prevent potential agglomeration in acidmedia. Suitable anti-adherents include talc, magnesium stearate, calciumstearate, stearic acid, hydrogenated vegetable oils, polyethyleneglycols, fumed silica, silicon dioxide, or combinations thereof.

Pore-forming agents serve to create pores or channels in the entericcoating after administration to a human. Suitable pore-forming agentsinclude sodium chloride, potassium chloride, sucrose, sorbitol,mannitol, polyethylene glycols (PEG), propylene glycol, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohols,methacrylic acid copolymers, poloxamers, or combinations thereof.

Many conventional coating excipients are described in the art. See e.g.,Rowe et al., Eds. Handbook of Pharmaceutical Excipients, 7^(th) ed.Royal Pharmaceutical Society, UK (2012).

In one embodiment described herein, the enteric coating comprisesmethacrylic acid and ethyl acrylate copolymer (e.g., EUDRAGIT® L100-55,Evonik), talc, triethyl citrate, sodium bicarbonate, colloidal silica,sodium lauryl sulfate, and water.

In one embodiment, adjusting the amount of enteric coating and the ratioof polymer to other components allows for tuning the release profile ofthe dosage form.

Subcoats can be applied to the soft capsules prior to coating to preventshell-coat interactions and improve coating adhesion to the capsule.Exemplary subcoatings can comprise polyvinylpyrrolidone, polyvinylalcohols, hydroxpropyl methylcellulose, polyethylene glycol, oils, orcombinations thereof.

Coatings, top coatings, or subcoatings are applied to the soft capsulesusing various methods know in the art. The coatings are typicallyprepared as suspensions and sprayed on capsules in perforated coatingpans through one or more spray nozzles at a specific temperature.Coating solutions or dispersion may be applied at spray rates between100 and 400 g/min. The spray rate may be proportionately higher forcoatings with higher solid content and lower for more dilutedispersions. In one embodiment, capsules are coated using a pan coater.After the enteric coating suspension is applied, the coated capsules aredried in the pan coater for a period of time at a specific temperature.

Another embodiment described herein comprises a subcoating that isapplied prior to applying an enteric coating. In one embodiment, thesubcoating comprises hydroxpropyl methylcellulose, methylcellulose,ethylcellulose, or a combination thereof.

Another embodiment described herein comprises a moisture barrier that isapplied as a top coating on the enteric coating. In one embodiment themoisture barrier comprises one or more polyvinyl alcohols andappropriate pharmaceutically acceptable excipients. In one embodimentthe moisture barrier comprises polyvinyl alcohol, sodium lauryl sulfate,glyceryl mono-caprylate-caprate, and talc. In one aspect, the moisturebarrier aids in preserving the cosmetic appearance of the dosage formsby preventing dimpling, sticking, or other processing or storage inducedblemishes.

Another embodiment described herein, the fumarate ester pharmaceuticalcomposition can comprise an enteric hard capsule shell comprising amatrix comprising a fumarate ester.

Another embodiment described herein, the fumarate ester pharmaceuticalcomposition can comprise a hard capsule shell comprising a matrixcomprising a fumarate ester.

The pharmaceutical compositions described herein can contain a matrixfill that is liquid, semi-solid, or solid. Capsules prepared asdescribed herein can contain hydrophobic solutions or suspensions, suchas vegetable oils, shortening, waxes, or combinations thereof. Thematrix fill can be formulated to prevent interaction with the capsuleshell components and release the pharmaceutical composition at aspecified rate.

One embodiment described herein, is a pharmaceutical compositioncomprising a matrix fill formulation comprising any of the formulationsshown in the Tables or Examples described herein. Any of the componentsin the formulations described herein, shown in the Tables, orillustrated in the Examples can be increased, decreased, combined,substituted, or omitted to provide for a formulation comprising about100% by weight. Such compositions are hereby disclosed as if they wereexpressly disclosed herein.

In one embodiment, the pharmaceutical compositions described hereinprovide a dosage form of one or more fumarate esters, or prodrugsthereof, for administration to a subject. The dosage form can beadministered, for example, to a subject, or a subject in need thereof.In one aspect, the subject is a mammal, or a mammal in need thereof. Inone aspect, the subject is a human, or human in need thereof. In oneaspect, the human or human in need thereof is a medical patient. In oneaspect, the human subject is a child (˜0-9 years old) or an adolescent(˜10-17 years old). In one aspect, the subject is from about 0 to about9 years of age. In another aspect, the human subject is from about 10years to about 17 years of age. In another aspect, the human subject isover 17 years of age. In another aspect, the human subject is an adult(18 years of age).

The dosage form can be administered, for example, 1×, 2×, 3×, 4×, 5×,6×, or even more times per day. One or more dosage forms can beadministered, for example, for 1, 2, 3, 4, 5, 6, 7 days, or even longer.One or more dosage forms can be administered, for example, for 1, 2, 3,4 weeks, or even longer. One or more dosage forms can be administered,for example, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, 1 year,2, years, 3 years, 4 years, 5 years, over 5 years, a decade, multipledecades, or even longer. One or more dosage forms can be administered ata regular interval until the subject or subject in need thereof, doesnot require treatment, prophylaxis, or amelioration of any disease orcondition including but not limited to, general autoimmune orneurodegenerative disorders.

In one embodiment, the pharmaceutical composition described herein isadministered in multiple doses simultaneously. For example, two or moreidentical doses are administered at one time. In another embodiment, twoor more different doses are administered at one time. Such dual ordifferent simultaneous doses can be used to provide an effective amountof the pharmaceutical composition to a subject in need thereof.

In another embodiment, the pharmaceutical compositions described hereinmay be used to treat, prevent, retard the progression of, delay theonset, ameliorate, reduce the symptoms of, or prophylaxis of generalautoimmune or neurodegenerative disorders. Neurodegenerative disorders,as used herein, include multiple sclerosis (MS), which includesrelapsing remitting multiple sclerosis (RRMS), secondary progressivemultiple sclerosis (SPMS), primary progressive multiple sclerosis(PPMS), progressive relapsing multiple sclerosis (PPvMS), amyotrophiclateral sclerosis (ALS), psoriasis, psoriatic arthritis, Alzheimer'sdisease, Parkinson's disease, or any combination thereof.

In one embodiment described herein, other conditions, disorders, ordiseases are controlled by administration of fumarate esters. Theadministration of pharmaceutical compositions comprising fumarateesters, as described herein, may be used for treating, preventing,retarding the progression of, delaying the onset, ameliorating, reducingthe symptoms of, or prophylaxis of general autoimmune orneurodegenerative disorders, including but not limited to, acutedermatitis, adrenal leukodystrophy, AGE-induced genome damage,Alexander's disease, alopecia areata (totalis and universalis), Alper'sdisease, Alzheimer's disease, amyotrophic lateral sclerosis, anginapectoris, arthritis, asthma, autoimmune diseases, balo concentricsclerosis, Behçet's syndrome, bullous pemphigoid, Canavan disease,cardiac insufficiency including left ventricular insufficiency, centralnervous system vasculitis, Charcot-Marie-Tooth disease, childhood ataxiawith central nervous system hypomyelination, chronic active (lupoid)hepatitis, chronic dermatitis, chronic idiopathic peripheral neuropathy,chronic obstructive pulmonary disease, contact dermatitis, Crohn'sdisease and cutaneous Crohn's disease, cutaneous lupus, cutaneoussarcoidosis, diabetic retinopathy, fibromyalgia, graft versus hostdisease, granuloma annulare, granulomas including annulare, Grave'sdisease, Hashimoto's thyroiditis, hepatitis C viral infection, herpessimplex viral infection, human immunodeficiency viral infection,Huntington's disease, inflammatory bowel disease, irritable boweldisorder, ischemia, juvenile-onset diabetes mellitus, Krabbe disease,lichen planus, macular degeneration, mitochondrial encephalomyopathy,monomelic amyotrophy, multiple sclerosis (MS), myocardial infarction,necrobiosis lipoidica, neurodegeneration with brain iron accumulation,neurodermatitis, neuromyelitis optica, neuropathic pain,neurosarcoidosis, NF-κB mediated diseases, optic neuritis, organtransplantation rejection, paraneoplastic syndromes, Parkinson'sdisease, Pelizaeus-Merzbacher disease, pemphigus, pernicious anemia,primary lateral sclerosis, progressive supranuclear palsy, psoriasis,psoriatic arthritis, pyoderma gangrenosum, radiation-induced dermatitis,radicular pain, radiculopathic pain, reperfusion injury, retinopathicpigmentosa, rheumatoid arthritis (RA), sarcoidosis, sarcoidosis,Schilder's disease, sciatic pain, sciatica, Sjögren's syndrome, subacutenecrotizing myelopathy, such as polyarthritis, Susac's syndrome,systemic lupus erythematosus (SLE), tumors, transverse myelitis,ulcerative colitis, or Zellweger syndrome.

One embodiment described herein comprises a method for orallyadministering a dosage form that provides a total amount of fumarateester of about 20 mg to about 1000 mg (e.g., ˜20-1000 mg), including allintegers and fractions within the specified range.

In one embodiment described herein, the fumarate ester (FAE) dosage formcan comprise, but is not limited to about 50 mg FAE, about 55 mg FAE,about 60 mg FAE, about 65 mg FAE, about 70 mg FAE, about 75 mg FAE,about 80 mg FAE, about 85 mg FAE, about 90 mg FAE, about 95 mg FAE,about 100 mg FAE, about 105 mg FAE, about 110 mg FAE, about 115 mg FAE,about 120 mg FAE, about 125 mg FAE, about 130 mg FAE, about 135 mg FAE,about 140 mg FAE, about 145 mg FAE, about 150 mg FAE, about 155 mg FAE,about 160 mg FAE, about 165 mg FAE, about 170 mg FAE, about 175 mg FAE,about 180 mg FAE, about 185 mg FAE, about 190 mg FAE, about 195 mg FAE,about 200 mg FAE, about 205 mg FAE, about 210 mg FAE, about 215 mg FAE,about 220 mg FAE, about 225 mg FAE, about 230 mg FAE, about 235 mg FAE,about 240 mg FAE, about 245 mg FAE, about 250 mg FAE, about 255 mg FAE,about 260 mg FAE, about 265 mg FAE, about 270 mg FAE, about 275 mg FAE,about 280 mg FAE, about 285 mg FAE, about 290 mg FAE, about 295 mg FAE,about 300 mg FAE, about 305 mg FAE, about 310 mg FAE, about 315 mg FAE,about 320 mg FAE, about 325 mg FAE, about 330 mg FAE, about 335 mg FAE,about 340 mg FAE, about 345 mg FAE, about 350 mg FAE, about 355 mg FAE,about 360 mg FAE, about 365 mg FAE, about 370 mg FAE, about 375 mg FAE,about 380 mg FAE, about 385 mg FAE, about 390 mg FAE, about 395 mg FAE,about 400 mg FAE, about 405 mg FAE, about 410 mg FAE, about 415 mg FAE,about 420 mg FAE, about 425 mg FAE, about 430 mg FAE, about 435 mg FAE,about 440 mg FAE, about 445 mg FAE, about 450 mg FAE, about 455 mg FAE,about 460 mg FAE, about 465 mg FAE, about 470 mg FAE, about 475 mg FAE,or about 480 mg FAE. In one embodiment, the foregoing doses comprise apartial dosage, e.g., including but not limited to one dose of a twice,thrice or quadrice daily regimen. In another embodiment, any of theforegoing doses comprise a total daily dosage. In another embodiment,any of the foregoing doses may be administered simultaneously, such astwo 95 mg FAE or two 100 mg FAE, to provide 190 mg or 200 mg FAE for aparticular dosing period.

In another embodiment described herein, the fumarate ester (FAE) dosageform can comprise, but is not limited to about 50 mg FAE, about 52 mgFAE, about 54 mg FAE, about 56 mg FAE, about 58 mg FAE, about 60 mg FAE,about 62 mg FAE, about 64 mg FAE, about 66 mg FAE, about 68 mg FAE,about 70 mg FAE, about 72 mg FAE, about 74 mg FAE, about 76 mg FAE,about 78 mg FAE, about 80 mg FAE, about 82 mg FAE, about 84 mg FAE,about 86 mg FAE, about 88 mg FAE, about 90 mg FAE, about 92 mg FAE,about 94 mg FAE, about 96 mg FAE, about 98 mg FAE, about 100 mg FAE,about 102 mg FAE, about 104 mg FAE, about 106 mg FAE, about 108 mg FAE,about 110 mg FAE, about 112 mg FAE, about 114 mg FAE, about 116 mg FAE,about 118 mg FAE, about 120 mg FAE, about 122 mg FAE, about 124 mg FAE,about 126 mg FAE, about 128 mg FAE, about 130 mg FAE, about 132 mg FAE,about 134 mg FAE, about 136 mg FAE, about 138 mg FAE, about 140 mg FAE,about 142 mg FAE, about 144 mg FAE, about 146 mg FAE, about 148 mg FAE,about 150 mg FAE, about 152 mg FAE, about 154 mg FAE, about 156 mg FAE,about 158 mg FAE, about 160 mg FAE, about 162 mg FAE, about 164 mg FAE,about 166 mg FAE, about 168 mg FAE, about 170 mg FAE, about 172 mg FAE,about 174 mg FAE, about 176 mg FAE, about 178 mg FAE, about 180 mg FAE,about 182 mg FAE, about 184 mg FAE, about 186 mg FAE, about 188 mg FAE,about 190 mg FAE, about 192 mg FAE, about 194 mg FAE, about 196 mg FAE,about 198 mg FAE, about 200 mg FAE, about 202 mg FAE, about 204 mg FAE,about 206 mg FAE, about 208 mg FAE, about 210 mg FAE, about 212 mg FAE,about 214 mg FAE, about 215 mg FAE, about 216 mg FAE, about 218 mg FAE,about 220 mg FAE, about 222 mg FAE, about 224 mg FAE, about 226 mg FAE,about 228 mg FAE, about 230 mg FAE, about 232 mg FAE, about 234 mg FAE,about 236 mg FAE, about 238 mg FAE, about 240 mg FAE, about 242 mg FAE,about 244 mg FAE, about 246 mg FAE, about 248 mg FAE, about 250 mg FAE,about 252 mg FAE, about 254 mg FAE, about 256 mg FAE, about 258 mg FAE,about 260 mg FAE, about 262 mg FAE, about 264 mg FAE, about 266 mg FAE,about 268 mg FAE, about 270 mg FAE, about 272 mg FAE, about 274 mg FAE,about 276 mg FAE, about 278 mg FAE, about 280 mg FAE, about 282 mg FAE,about 284 mg FAE, about 286 mg FAE, about 288 mg FAE, about 290 mg FAE,about 292 mg FAE, about 294 mg FAE, about 296 mg FAE, about 298 mg FAE,about 300 mg FAE, about 302 mg FAE, about 304 mg FAE, about 306 mg FAE,about 308 mg FAE, about 310 mg FAE, about 312 mg FAE, about 314 mg FAE,about 316 mg FAE, about 318 mg FAE, about 320 mg FAE, about 322 mg FAE,about 324 mg FAE, about 326 mg FAE, about 328 mg FAE, about 330 mg FAE,about 332 mg FAE, about 334 mg FAE, about 336 mg FAE, about 338 mg FAE,about 340 mg FAE, about 342 mg FAE, about 344 mg FAE, about 346 mg FAE,about 348 mg FAE, about 350 mg FAE, about 352 mg FAE, about 354 mg FAE,about 356 mg FAE, about 358 mg FAE, about 360 mg FAE, about 362 mg FAE,about 364 mg FAE, about 366 mg FAE, about 368 mg FAE, about 370 mg FAE,about 372 mg FAE, about 374 mg FAE, about 376 mg FAE, about 378 mg FAE,about 380 mg FAE, about 382 mg FAE, about 384 mg FAE, about 386 mg FAE,about 388 mg FAE, about 390 mg FAE, about 392 mg FAE, about 394 mg FAE,about 396 mg FAE, about 398 mg FAE, about 400 mg FAE, about 402 mg FAE,about 404 mg FAE, about 406 mg FAE, about 408 mg FAE, about 410 mg FAE,about 412 mg FAE, about 414 mg FAE, about 416 mg FAE, about 418 mg FAE,about 420 mg FAE, about 422 mg FAE, about 424 mg FAE, about 426 mg FAE,about 428 mg FAE, about 430 mg FAE, about 432 mg FAE, about 434 mg FAE,about 436 mg FAE, about 438 mg FAE, about 440 mg FAE, about 442 mg FAE,about 444 mg FAE, about 446 mg FAE, about 448 mg FAE, about 450 mg FAE,about 452 mg FAE, about 454 mg FAE, about 456 mg FAE, about 458 mg FAE,about 460 mg FAE, about 462 mg FAE, about 464 mg FAE, about 466 mg FAE,about 468 mg FAE, about 470 mg FAE, about 472 mg FAE, about 474 mg FAE,about 476 mg FAE, about 478 mg FAE, or about 480 mg FAE. In oneembodiment, the foregoing doses comprise a partial dosage, e.g.,including but not limited to one dose of a twice thrice, or quadricedaily regimen. In another embodiment, any of the foregoing dosescomprise a total daily dosage. In another embodiment, any of theforegoing doses may be administered simultaneously, such as two 95 mgFAE or two 100 mg FAE, to provide 190 mg or 200 mg FAE for a particulardosing period.

In one embodiment, the daily dosage is about 80 mg FAE to about 460 mgFAE including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 90 mg FAE to about 110 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 95 mg FAE to about 100 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 90 mg FAE to about 220 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 100 mg FAE to about 200 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 100 mg FAE to about 220 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 170 mg FAE to about 200 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 180 mg FAE to about 200 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 190 mg FAE to about 200 mgFAE, including all integers and fractions within the specified range. Inone embodiment, the daily dosage is about 200 mg FAE to about 220 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 380 mg FAE to about 400 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 320 mg FAE to about 460 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 400 mg FAE to about 460 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 460 mg FAE. The totaldaily dose may be administered in any number of individual dosage formsthat cumulatively total the daily dose. For example, four 95 mg FAEdosage forms may be administered in a regimen of two dosage forms in themorning and two in the evening for a total daily dose of 380 mg FAE.Alternatively, four 95 mg FAE dosage forms may be administered QID(e.g., every six hours) for a total daily dose of 380 mg FAE.

In another embodiment, the daily dosage can comprise, but is not limitedto, a total amount of FAE of about 80 mg FAE, about 82 mg FAE, about 84mg FAE, about 86 mg FAE, about 88 mg FAE, about 90 mg FAE, about 92 mgFAE, about 94 mg FAE, about 96 mg FAE, about 98 mg FAE, about 100 mgFAE, about 102 mg FAE, about 104 mg FAE, about 106 mg FAE, about 108 mgFAE, about 110 mg FAE, about 112 mg FAE, about 114 mg FAE, about 116 mgFAE, about 118 mg FAE, about 120 mg FAE, about 122 mg FAE, about 124 mgFAE, about 126 mg FAE, about 128 mg FAE, about 130 mg FAE, about 132 mgFAE, about 134 mg FAE, about 136 mg FAE, about 138 mg FAE, about 140 mgFAE, about 142 mg FAE, about 144 mg FAE, about 146 mg FAE, about 148 mgFAE, about 150 mg FAE, about 152 mg FAE, about 154 mg FAE, about 156 mgFAE, about 158 mg FAE, about 160 mg FAE, about 162 mg FAE, about 164 mgFAE, about 166 mg FAE, about 168 mg FAE, about 170 mg FAE, about 172 mgFAE, about 174 mg FAE, about 176 mg FAE, about 178 mg FAE, about 180 mgFAE, about 182 mg FAE, about 184 mg FAE, about 186 mg FAE, about 188 mgFAE, about 190 mg FAE, about 192 mg FAE, about 194 mg FAE, about 196 mgFAE, about 198 mg FAE, about 200 mg FAE, about 202 mg FAE, about 204 mgFAE, about 206 mg FAE, about 208 mg FAE, about 210 mg FAE, about 212 mgFAE, about 214 mg FAE, about 215 mg FAE, about 216 mg FAE, about 218 mgFAE, about 220 mg FAE, about 222 mg FAE, about 224 mg FAE, about 226 mgFAE, about 228 mg FAE, about 230 mg FAE, about 232 mg FAE, about 234 mgFAE, about 236 mg FAE, about 238 mg FAE, about 240 mg FAE, about 242 mgFAE, about 244 mg FAE, about 246 mg FAE, about 248 mg FAE, about 250 mgFAE, about 252 mg FAE, about 254 mg FAE, about 256 mg FAE, about 258 mgFAE, about 260 mg FAE, about 262 mg FAE, about 264 mg FAE, about 266 mgFAE, about 268 mg FAE, about 270 mg FAE, about 272 mg FAE, about 274 mgFAE, about 276 mg FAE, about 278 mg FAE, about 280 mg FAE, about 282 mgFAE, about 284 mg FAE, about 286 mg FAE, about 288 mg FAE, about 290 mgFAE, about 292 mg FAE, about 294 mg FAE, about 296 mg FAE, about 298 mgFAE, about 300 mg FAE, about 302 mg FAE, about 304 mg FAE, about 306 mgFAE, about 308 mg FAE, about 310 mg FAE, about 312 mg FAE, about 314 mgFAE, about 316 mg FAE, about 318 mg FAE, about 320 mg FAE, about 322 mgFAE, about 324 mg FAE, about 326 mg FAE, about 328 mg FAE, about 330 mgFAE, about 332 mg FAE, about 334 mg FAE, about 336 mg FAE, about 338 mgFAE, about 340 mg FAE, about 342 mg FAE, about 344 mg FAE, about 346 mgFAE, about 348 mg FAE, about 350 mg FAE, about 352 mg FAE, about 354 mgFAE, about 356 mg FAE, about 358 mg FAE, about 360 mg FAE, about 362 mgFAE, about 364 mg FAE, about 366 mg FAE, about 368 mg FAE, about 370 mgFAE, about 372 mg FAE, about 374 mg FAE, about 376 mg FAE, about 378 mgFAE, about 380 mg FAE, about 382 mg FAE, about 384 mg FAE, about 386 mgFAE, about 388 mg FAE, about 390 mg FAE, about 392 mg FAE, about 394 mgFAE, about 396 mg FAE, about 398 mg FAE, about 400 mg FAE, about 402 mgFAE, about 404 mg FAE, about 406 mg FAE, about 408 mg FAE, about 410 mgFAE, about 412 mg FAE, about 414 mg FAE, about 416 mg FAE, about 418 mgFAE, about 420 mg FAE, about 422 mg FAE, about 424 mg FAE, about 426 mgFAE, about 428 mg FAE, about 430 mg FAE, about 432 mg FAE, about 434 mgFAE, about 436 mg FAE, about 438 mg FAE, about 440 mg FAE, about 442 mgFAE, about 444 mg FAE, about 446 mg FAE, about 448 mg FAE, about 450 mgFAE, about 452 mg FAE, about 454 mg FAE, about 456 mg FAE, about 458 mgFAE, about 460 mg FAE, about 462 mg FAE, about 464 mg FAE, about 466 mgFAE, about 468 mg FAE, about 470 mg FAE, about 472 mg FAE, about 474 mgFAE, about 476 mg FAE, about 478 mg FAE, or about 480 mg FAE. The dailydosage can contain a total amount of fumarate ester effective fortreatment of retarding the progression of, prophylaxis of delaying theonset of, amelioration of, or reducing symptoms of multiple sclerosis orpsoriasis or other neurodegenerative disorders. In one aspect, the dailydosage is about 380 mg FAE to about 420 mg FAE. In another aspect, thedaily dosage is about 380 mg FAE to about 400 mg FAE. In another aspect,the daily dosage is about 380 mg FAE. In another aspect, the dailydosage is about 400 mg FAE.

In one embodiment, the amount of fumarate ester can comprise about 80 mgto about 500 mg (e.g., 80-500 mg) of fumarate ester, including allintegers and fractions within the specified range. In one embodiment,the amount can comprise, but is not limited to, about 80 mg to about 480mg FAE, including all integers and fractions within the specified range.In one embodiment, the amount of fumarate ester can comprise about 80 mgFAE to about 85 mg FAE, about 85 mg FAE to about 90 mg FAE, about 85 mgFAE to about 100 mg FAE, about 90 mg FAE to about 95 mg FAE, about 90 mgFAE to about 100 mg FAE, about 90 mg FAE to about 105 mg FAE, about 90mg FAE to about 110 mg FAE, about 90 mg FAE to about 115 mg FAE, about90 mg FAE to about 120 mg FAE, about 95 mg FAE to about 100 mg FAE,about 95 mg FAE to about 110 mg FAE, about 95 mg FAE to about 120 mgFAE, about 95 mg FAE to about 190 mg FAE, about 95 mg FAE to about 200mg FAE, about 100 mg FAE to about 105 mg FAE, about 100 mg FAE to about110 mg FAE, about 100 mg FAE to about 115 mg FAE, about 100 mg FAE toabout 120 mg FAE, about 100 mg FAE to about 180 mg FAE, about 100 mg FAEto about 190 mg FAE, about 100 mg FAE to about 200 mg FAE, about 100 mgFAE to about 210 mg FAE, about 100 mg FAE to about 220 mg FAE, about 100mg FAE to about 230 mg FAE, about 100 mg FAE to about 240 mg FAE, about100 mg FAE to about 400 mg FAE, about 100 mg FAE to about 420 mg FAE,about 100 mg FAE to about 430 mg FAE, about 100 mg FAE to about 440 mgFAE, about 100 mg FAE to about 460 mg FAE, about 100 mg FAE to about 480mg FAE, about 105 mg FAE to about 110 mg FAE, about 105 mg FAE to about115 mg FAE, about 105 mg FAE to about 120 mg FAE, about 105 mg FAE toabout 200 mg FAE, about 105 mg FAE to about 210 mg FAE, about 105 mg FAEto about 220 mg FAE, about 105 mg FAE to about 230 mg FAE, about 105 mgFAE to about 240 mg FAE, about 105 mg FAE to about 400 mg FAE, about 105mg FAE to about 420 mg FAE, about 105 mg FAE to about 430 mg FAE, about105 mg FAE to about 440 mg FAE, about 105 mg FAE to about 460 mg FAE,about 105 mg FAE to about 480 mg FAE, about 110 mg FAE to about 115 mgFAE, about 110 mg FAE to about 120 mg FAE, about 110 mg FAE to about 200mg FAE, about 110 mg FAE to about 210 mg FAE, about 110 mg FAE to about220 mg FAE, about 110 mg FAE to about 230 mg FAE, about 110 mg FAE toabout 240 mg FAE, about 110 mg FAE to about 400 mg FAE, about 110 mg FAEto about 420 mg FAE, about 120 mg FAE to about 430 mg FAE, about 110 mgFAE to about 440 mg FAE, about 110 mg FAE to about 460 mg FAE, about 110mg FAE to about 480 mg FAE, about 115 mg FAE to about 120 mg FAE, about115 mg FAE to about 200 mg FAE, about 115 mg FAE to about 210 mg FAE,about 115 mg FAE to about 220 mg FAE, about 115 mg FAE to about 230 mgFAE, about 115 mg FAE to about 240 mg FAE, about 115 mg FAE to about 400mg FAE, about 115 mg FAE to about 420 mg FAE, about 115 mg FAE to about430 mg FAE, about 115 mg FAE to about 440 mg FAE, about 115 mg FAE toabout 460 mg FAE, about 115 mg FAE to about 480 mg FAE, about 120 mg FAEto about 200 mg FAE, about 120 mg FAE to about 210 mg FAE, about 120 mgFAE to about 220 mg FAE, about 120 mg FAE to about 230 mg FAE, about 120mg FAE to about 240 mg FAE, about 120 mg FAE to about 400 mg FAE, about120 mg FAE to about 420 mg FAE, about 120 mg FAE to about 430 mg FAE,about 120 mg FAE to about 440 mg FAE, about 120 mg FAE to about 460 mgFAE, about 120 mg FAE to about 480 mg FAE, about 180 mg FAE to about 200mg FAE, about 190 mg FAE to about 200 mg FAE, about 190 mg FAE to about380 mg FAE, about 190 mg FAE to about 400 mg FAE, about 200 mg FAE toabout 210 mg FAE, about 200 mg FAE to about 220 mg FAE, about 200 mg FAEto about 230 mg FAE, about 200 mg FAE to about 240 mg FAE, about 200 mgFAE to about 400 mg FAE, about 200 mg FAE to about 420 mg FAE, about 200mg FAE to about 430 mg FAE, about 200 mg FAE to about 440 mg FAE, about200 mg FAE to about 460 mg FAE, about 200 mg FAE to about 480 mg FAE,about 210 mg FAE to about 220 mg FAE, about 210 mg FAE to about 230 mgFAE, about 210 mg FAE to about 240 mg FAE, about 210 mg FAE to about 400mg FAE, about 210 mg FAE to about 420 mg FAE, about 210 mg FAE to about430 mg FAE, about 210 mg FAE to about 440 mg FAE, about 210 mg FAE toabout 460 mg FAE, about 210 mg FAE to about 480 mg FAE, about 220 mg FAEto about 230 mg FAE, about 220 mg FAE to about 240 mg FAE, about 220 mgFAE to about 400 mg FAE, about 220 mg FAE to about 420 mg FAE, about 220mg FAE to about 430 mg FAE, about 220 mg FAE to about 440 mg FAE, about220 mg FAE to about 460 mg FAE, about 220 mg FAE to about 480 mg FAE,about 230 mg FAE to about 240 mg FAE, about 230 mg FAE to about 400 mgFAE, about 230 mg FAE to about 420 mg FAE, about 230 mg FAE to about 430mg FAE, about 230 mg FAE to about 440 mg FAE, about 230 mg FAE to about460 mg FAE, about 230 mg FAE to about 480 mg FAE, about 240 mg FAE toabout 400 mg FAE, about 240 mg FAE to about 420 mg FAE, about 240 mg FAEto about 430 mg FAE, about 240 mg FAE to about 440 mg FAE, about 240 mgFAE to about 460 mg FAE, about 240 mg FAE to about 480 mg FAE, about 380mg FAE to about 400 mg FAE, about 380 mg FAE to about 420 mg FAE, about400 mg FAE to about 410 mg FAE, about 400 mg FAE to about 420 mg FAE,about 400 mg FAE to about 430 mg FAE, about 400 mg FAE to about 440 mgFAE, about 400 mg FAE to about 460 mg FAE, about 400 mg FAE to about 480mg FAE, about 420 mg FAE to about 430 mg FAE, about 420 mg FAE to about440 mg FAE, about 420 mg FAE to about 460 mg FAE, about 420 mg FAE toabout 480 mg FAE, about 430 mg FAE to about 440 mg FAE, about 430 mg FAEto about 460 mg FAE, about 430 mg FAE to about 480 mg FAE, about 440 mgFAE to about 460 mg FAE, about 440 mg FAE to about 480 mg FAE, or about460 mg FAE to about 480 mg FAE, including all integers and fractionswithin the specified ranges.

In one embodiment described herein, the pharmaceutical compositioncomprises from about 80 mg FAE to about 119 FAE including each integerwithin the specified range. In one embodiment described herein, thepharmaceutical composition comprises about 80 mg FAE, about 81 mg FAE,about 82 mg FAE, about 893 mg FAE, about 84 mg FAE, about 85 mg FAE,about 86 mg FAE, about 87 mg FAE, about 88 mg FAE, about 89 mg FAE,about 90 mg FAE, about 91 mg FAE, about 92 mg FAE, about 93 mg FAE,about 94 mg FAE, about 95 mg FAE, about 96 mg FAE, about 97 mg FAE,about 98 mg FAE, about 99 mg FAE, about 100 mg FAE, about 101 mg FAE,about 102 mg FAE, about 103 mg FAE, about 104 mg FAE, about 105 mg FAE,about 106 mg FAE, about 107 mg FAE, about 108 mg FAE, about 109 mg FAE,about 110 mg FAE, about 111 mg FAE, about 112 mg FAE, about 113 mg FAE,about 114 mg FAE, about 115 mg FAE, about 116 mg FAE, about 117 mg FAE,about 118 mg FAE, or about 119 mg FAE.

In one embodiment described herein, the pharmaceutical compositioncomprises from about 180 mg FAE to about 238 FAE including each integerwithin the specified range. In one embodiment described herein, thepharmaceutical composition comprises about 180 mg FAE, about 182 mg FAE,about 184 mg FAE, about 186 mg FAE, about 188 mg FAE, about 190 mg FAE,about 192 mg FAE, about 194 mg FAE, about 196 mg FAE, about 198 mg FAE,about 200 mg FAE, about 202 mg FAE, about 204 mg FAE, about 206 mg FAE,about 208 mg FAE, about 210 mg FAE, about 212 mg FAE, about 214 mg FAE,about 216 mg FAE, about 218 mg FAE, about 220 mg FAE, about 222 mg FAE,about 224 mg FAE, about 226 mg FAE, about 228 mg FAE, about 230 mg FAE,about 232 mg FAE, about 234 mg FAE, about 236 mg FAE, or about 238 mgFAE.

In one embodiment described herein, the pharmaceutical compositioncomprises from about 360 mg FAE to about 476 FAE including each integerwithin the specified range. In one embodiment described herein, thepharmaceutical composition comprises about 360 mg FAE, about 362 mg FAE,about 364 mg FAE, about 368 mg FAE, about 372 mg FAE, about 376 mg FAE,about 380 mg FAE, about 384 mg FAE, about 388 mg FAE, about 392 mg FAE,about 396 mg FAE, about 400 mg FAE, about 404 mg FAE, about 408 mg FAE,about 412 mg FAE, about 416 mg FAE, about 420 mg FAE, about 424 mg FAE,about 428 mg FAE, about 432 mg FAE, about 436 mg FAE, about 440 mg FAE,about 444 mg FAE, about 448 mg FAE, about 452 mg FAE, about 456 mg FAE,about 460 mg FAE, about 464 mg FAE, about 468 mg FAE, about 472 mg FAE,or about 476 mg FAE.

In one embodiment described herein, the pharmaceutical compositioncomprises from about 90 mg FAE to about 476 FAE including each integerwithin the specified range. In one embodiment described herein, thepharmaceutical composition comprises about 90 mg FAE, about 91 mg FAE,about 92 mg FAE, about 93 mg FAE, about 94 mg FAE, about 95 mg FAE,about 96 mg FAE, about 97 mg FAE, about 98 mg FAE, about 99 mg FAE,about 100 mg FAE, about 101 mg FAE, about 102 mg FAE, about 103 mg FAE,about 104 mg FAE, about 105 mg FAE, about 106 mg FAE, about 107 mg FAE,about 108 mg FAE, about 109 mg FAE, about 110 mg FAE, about 111 mg FAE,about 112 mg FAE, about 113 mg FAE, about 114 mg FAE, about 115 mg FAE,about 116 mg FAE, about 117 mg FAE, about 118 mg FAE, about 119 mg FAE,about 180 mg FAE, about 182 mg FAE, about 184 mg FAE, about 186 mg FAE,about 188 mg FAE, about 190 mg FAE, about 192 mg FAE, about 194 mg FAE,about 196 mg FAE, about 198 mg FAE, about 200 mg FAE, about 202 mg FAE,about 204 mg FAE, about 206 mg FAE, about 208 mg FAE, about 210 mg FAE,about 212 mg FAE, about 214 mg FAE, about 216 mg FAE, about 218 mg FAE,about 220 mg FAE, about 222 mg FAE, about 224 mg FAE, about 226 mg FAE,about 228 mg FAE, about 230 mg FAE, about 232 mg FAE, about 234 mg FAE,about 236 mg FAE, about 238 mg FAE, about 360 mg FAE, about 364 mg FAE,about 368 mg FAE, about 372 mg FAE, about 376 mg FAE, about 380 mg FAE,about 384 mg FAE, about 388 mg FAE, about 392 mg FAE, about 396 mg FAE,about 400 mg FAE, about 404 mg FAE, about 408 mg FAE, about 412 mg FAE,about 416 mg FAE, about 420 mg FAE, about 424 mg FAE, about 428 mg FAE,about 432 mg FAE, about 436 mg FAE, about 440 mg FAE, about 444 mg FAE,about 448 mg FAE, about 452 mg FAE, about 456 mg FAE, about 460 mg FAE,about 464 mg FAE, about 468 mg FAE, about 472 mg FAE, or about 476 mgFAE.

In one embodiment, the amount of fumarate ester can comprise about 85 mgto about 100 mg FAE, about 85 mg to about 110 mg FAE, about 85 mg toabout 115 mg FAE, about 90 mg to about 100 mg FAE, about 90 mg to about110 mg FAE, about 90 mg to about 115 mg FAE, about 90 mg to about 120 mgFAE, about 90 mg to about 200 mg FAE, about 90 mg to about 220 mg FAE,about 90 mg to about 230 mg FAE, about 95 mg to about 100 mg FAE, about95 mg to about 110 mg FAE, about 95 mg to about 120 mg FAE, about 95 mgto about 200 mg FAE, about 95 mg to about 380 mg FAE, about 95 mg toabout 400 mg FAE, about 100 mg to about 105 mg FAE, about 100 mg toabout 110 mg FAE, about 100 mg to about 115 mg FAE, about 100 mg toabout 120 mg FAE, about 100 mg to about 205 mg FAE, about 100 mg toabout 210 mg FAE, about 100 mg to about 215 mg FAE, about 100 mg toabout 220 mg FAE, about 100 mg to about 230 mg FAE, about 100 mg toabout 380 mg FAE, about 100 mg to about 400 mg FAE, about 170 mg toabout 220 mg FAE, about 180 mg to about 200 mg FAE, about 180 mg toabout 220 mg FAE, about 180 mg to about 380 mg FAE, about 180 mg toabout 400 mg FAE, about 190 mg to about 200 mg FAE, about 190 mg toabout 220 mg FAE, about 190 mg to about 380 mg FAE, about 190 mg toabout 400 mg FAE, about 200 mg to about 210 mg FAE, about 200 mg toabout 212 mg FAE, about 200 mg to about 214 mg FAE, about 200 mg toabout 216 mg FAE, about 200 mg to about 218 mg FAE, about 200 mg toabout 220 mg FAE, about 200 mg to about 225 mg FAE, about 200 mg toabout 230 mg FAE, about 200 mg to about 340 mg FAE, about 200 mg toabout 380 mg FAE, about 200 mg to about 400 mg FAE, about 200 mg toabout 420 mg FAE, about 200 mg to about 430 mg FAE, about 340 mg toabout 430 mg FAE, about 340 mg to about 460 mg FAE, about 380 mg toabout 400 mg FAE, about 380 mg to about 410 mg FAE, about 380 mg toabout 420 mg FAE, or about 380 mg to about 430 mg FAE.

In another embodiment, the effective amount of fumarate ester cancomprise, but is not limited to, about 70 mg FAE to about 480 mg FAE(e.g., 70-480 mg FAE), including all integers and fractions within thespecified range. In one aspect, the daily effective amount of fumarateester can comprise, but is not limited to, an effective amount of about70 mg to about 90 mg FAE, about 75 mg to about 95 mg FAE, about 80 mg toabout 100 mg FAE, about 85 mg to about 105 mg FAE, about 90 mg to about100 mg FAE, about 90 mg to about 105 mg FAE, about 90 mg to about 100 mgFAE, about 95 mg to about 100 mg FAE, about 95 mg to about 108 mg FAE,about 100 mg to about 110 mg FAE, about 100 mg to about 115 mg FAE,about 100 mg to about 120 mg FAE, about 105 mg to about 110 mg FAE,about 105 mg to about 115 mg FAE, about 105 mg to about 120 mg FAE,about 105 mg to about 125 mg FAE, about 110 mg to about 120 mg FAE,about 110 mg to about 125 mg FAE, about 115 mg FAE to about 120 mg FAE,about 115 mg FAE to about 125 mg FAE, about 100 mg to about 200 mg FAE,about 105 mg to about 210 mg FAE, about 110 mg to about 220 mg FAE,about 115 mg FAE to about 230 mg FAE, about 120 mg to about 240 mg FAE,about 180 mg to about 200 mg FAE, about 180 mg to about 220 mg FAE,about 200 mg to about 210 mg FAE, about 200 mg to about 220 mg FAE,about 210 mg to about 240 mg FAE, about 220 mg to about 250 mg FAE,about 380 mg to about 400 mg FAE, about 400 mg to about 420 mg FAE,about 400 mg to about 430 mg FAE, about 400 mg to about 440 mg FAE,about 400 mg to about 450 mg FAE, about 400 mg to about 460 mg FAE,about 400 mg to about 480 mg FAE, about 410 mg to about 420 mg FAE,about 410 mg to about 430 mg FAE, about 410 mg to about 440 mg FAE,about 410 mg to about 450 mg FAE, about 410 mg to about 460 mg FAE,about 410 mg to about 480 mg FAE, about 420 mg to about 430 mg FAE,about 420 mg to about 440 mg FAE, about 420 mg to about 450 mg FAE,about 420 mg to about 460 mg FAE, about 420 mg to about 480 mg FAE,about 425 mg to about 430 mg FAE, about 425 mg to about 440 mg FAE,about 425 mg to about 450 mg FAE, about 425 mg to about 460 mg FAE,about 425 mg to about 480 mg FAE, about 430 mg to about 440 mg FAE,about 430 mg to about 450 mg FAE, about 430 mg to about 460 mg FAE,about 430 mg to about 480 mg FAE, about 440 mg to about 450 mg FAE,about 440 mg to about 460 mg FAE, or about 440 mg to about 480 mg FAE,including all integers and fractions within the specified ranges.

In one embodiment, the daily effective amount of fumarate ester cancomprise about 85 mg to about 118 mg FAE, about 90 mg to about 105 mgFAE, about 90 mg to about 110 mg FAE, about 90 mg to about 115 mg FAE,about 90 mg to about 120 mg FAE, about 90 mg to about 230 mg FAE, about100 mg to about 105 mg FAE, about 100 mg to about 107 mg FAE, about 100mg to about 108 mg FAE, about 100 mg to about 110 mg FAE, about 100 mgto about 115 mg FAE, about 100 mg to about 120 mg FAE, about 100 mg toabout 205 mg FAE, about 100 mg to about 210 mg FAE, about 100 mg toabout 215 mg FAE, about 100 mg to about 220 mg FAE, about 100 mg toabout 230 mg FAE, about 170 mg to about 230 mg FAE, about 200 mg toabout 210 mg FAE, about 200 mg to about 212 mg FAE, about 200 mg toabout 214 mg FAE, about 200 mg to about 215 mg FAE, about 200 mg toabout 216 mg FAE, about 200 mg to about 218 mg FAE, about 200 mg toabout 220 mg FAE, about 200 mg to about 225 mg FAE, about 200 mg toabout 230 mg FAE, about 200 mg to about 340 mg FAE, about 200 mg toabout 430 mg FAE, about 340 mg to about 430 mg FAE, or about 340 mg toabout 460 mg FAE.

In one embodiment described herein, the pharmaceutical compositionsdescribed herein are indicated for the treatment of patients withrelapsing forms of multiple sclerosis. Another embodiment describedherein is a method for treating a patient with a relapsing form ofmultiple sclerosis comprising the administration of a dose of a fumarateester as described herein. In one aspect, the fumarate ester is DMF,MMF, or a combination thereof. In another aspect, the dose is betweenabout 85 mg FAE and about 120 mg FAE, including each integer within thespecified range. In another aspect, the total daily dose is betweenabout 100 mg FAE and about 230 mg FAE, including each integer within thespecified range. In another aspect, the total daily dose is betweenabout 170 mg FAE and about 230 mg FAE, including each integer within thespecified range. In another aspect, the total daily dose is betweenabout 340 mg FAE and about 460 mg FAE, including each integer within thespecified range. In one embodiment the total daily dose is about 210 mgFAE, about 211 mg FAE, about 212 mg FAE, about 213 mg FAE, about 214 mgFAE, about 215 mg FAE, about 216 mg FAE, about 217 mg FAE, about 218 mgFAE, about 219 mg FAE, or about 220 mg FAE. In one embodiment the totaldaily dose is about 420 mg FAE, about 422 mg FAE, about 424 mg FAE,about 426 mg FAE, about 428 mg FAE, about 430 mg FAE, about 432 mg FAE,about 434 mg FAE, about 436 mg FAE, about 438 mg FAE, or about 440 mgFAE.

In one embodiment described herein, the FAE may comprise a solution orsuspension having an active pharmaceutical ingredient load (e.g., drugload) of about 1% to about 65% by weight, including all integers andfractions within the specified range. In one embodiment, the drug loadcan comprise about 10% to about 45% by weight, including all integersand fractions within the specified range. In one embodiment, the drugload can comprise about 12% to about 16% by weight, including allintegers and fractions within the specified range. In one embodiment,the drug load can comprise about 24% to about 32% by weight, includingall integers and fractions within the specified range. In oneembodiment, the drug load can comprise about 20% to about 22% by weight,including all integers and fractions within the specified range. In oneembodiment, the drug load can comprise about 20% to about 50% by weight,including all integers and fractions within the specified range. In oneembodiment, the drug load can comprise about 40% to about 43% by weight,including all integers and fractions within the specified range. In oneembodiment, the drug load can comprise about 25% to about 45% by weight,including all integers and fractions within the specified range. In oneembodiment, the drug load can comprise about 29% to about 43% by weight,including all integers and fractions within the specified range. In oneembodiment, the drug load can comprise about 48% to about 64% by weight,including all integers and fractions within the specified range. In oneembodiment, the drug load can comprise about 1%, about 2%, about 2.5%,about 5%, about 10%, about 15%, about 20%, about 25%, about 29% about30%, about 35%, about 40%, about 42%, about 45%, about 40%, about 50%,about 60%, about 65%, or even higher, by weight. In one embodiment, thedrug load can comprise about 11.3%, 11.7%, 12.0%, 12.1%, 12.4%, 12.6%,12.7%, 12.9%, 13.1%, 13.3%, 13.6%, 13.8%, 14.1%, 14.2%, 14.3%, 14.4%,14.6%, 14.8%, 14.9%, 15.0%, 15.2%, 15.3%, 15.4%, 15.8%, 15.9%, 16.0%,16.5%, 16.6%, 16.7%, 17.1%, 17.2%, 17.3%, 17.8%, 17.9%, 18.0%, 22.7%,23.4%, 24.0%, 24.3%, 24.8%, 25.2%, 25.3%, 25.7%, 26.2%, 26.7%, 27.1%,27.2%, 27.6%, 27.7%, 28.1%, 28.3%, 28.5%, 28.6%, 28.7%, 28.8%, 29.2%,29.5%, 29.6%, 29.7%, 29.8%, 30.0%, 30.4%, 30.6%, 30.7%, 30.8%, 30.9%,31.7%, 31.9%, 32.0%, 32.9%, 33.1%, 33.2%, 33.3%, 34.2%, 34.4%, 34.6%,35.7%, 35.8%, 36.0%, 40.0%, 42.8%, 43.0%, 43.2%, 53.3%, 56.0%, 57.6%,58.7%, 61.3%, or 64.0% FAE, each by weight. In one embodiment, the drugload can comprise about 34% FAE, by weight.

In one embodiment described herein, pharmaceutical composition cancomprise about 0.4 mmol FAE to about 4.0 mmol FAE, including allintegers and fractions within the specified range. In one embodiment,the pharmaceutical composition comprises 0.4 mmol FAE, 0.5 mmol FAE, 0.6mmol FAE, 0.7 mmol FAE, 0.8 mmol FAE, 0.9 mmol FAE, 1.0 mmol FAE, 1.1mmol FAE, 1.2 mmol FAE, 1.3 mmol FAE, 1.4 mmol FAE, 1.5 mmol FAE, 1.6mmol FAE, 1.7 mmol FAE, 1.8 mmol FAE, 1.9 mmol FAE, 2.0 mmol FAE, 2.1mmol FAE, 2.2 mmol FAE, 2.3 mmol FAE, 2.4 mmol FAE, 2.5 mmol FAE, 2.6mmol FAE, 2.7 mmol FAE, 2.8 mmol FAE, 2.9 mmol FAE, 3.0 mmol FAE, 3.1mmol FAE, 3.2 mmol FAE, 3.3 mmol FAE, 3.4 mmol FAE, 3.5 mmol FAE, 3.6mmol FAE, 3.7 mmol FAE, 3.8 mmol FAE, 3.9 mmol FAE, or 4.0 mmol FAE. Inone embodiment, the pharmaceutical composition comprises about 0.7 mmolFAE to about 1.6 mmol FAE. In one aspect, the pharmaceutical compositioncomprises about 0.7 mmol FAE. In another aspect, the pharmaceuticalcomposition comprises about 0.8 mmol FAE. In another aspect, thepharmaceutical composition comprises about 1.5 mmol FAE.

In another embodiment described herein, the effective dose of fumarateester for treating multiple sclerosis or psoriasis is about 2.8 mmoleFAE to about 3.1 mmol FAE. In one aspect the effective dose of fumarateester is about 2.8. In another aspect the effective dose of fumarateester is about 3.1.

Another embodiment described herein is a pharmaceutical dosage formcomprising any one of the pharmaceutical compositions described hereinfor administration to a subject having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis, comprising a therapeutically effective amount of one or morefumarate esters, wherein the administration is sufficient to achieve areduction of about 0.224 annualized relapse rate relative to baseline inthe subject without substantially inducing one or more of flushing,abdominal pain, diarrhea, and nausea in the subject; and wherein theadministration does not require titration of the pharmaceuticalcomposition.

Another embodiment described herein is a method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,or reducing the symptoms of multiple sclerosis or psoriasis comprisingthe administration of a therapeutically effective amount of one or morefumarate esters comprising any one of the pharmaceutical compositionsdescribed herein to a subject with multiple sclerosis, wherein theadministration is sufficient to achieve a reduction of about 0.224annualized relapse rate relative to baseline in the subject withoutsubstantially inducing one or more of flushing, abdominal pain,diarrhea, and nausea in the subject. In one aspect, after administrationof any one the pharmaceutical compositions described herein, the subjectexperiences one or more of flushing, abdominal pain, diarrhea, andnausea at a rate of less than about 10%. In another aspect, the endpointmay be less than about 2%, about 5%, about 10%, about 15%, about 20%,about 25%, about 30%, about 35%, about 45%, about 50%, or greater thanabout 50%.

Another embodiment described herein is a pharmaceutical composition anda method for treating, retarding the progression of, delaying the onsetof, prophylaxis of, amelioration of, or reducing the symptoms of ageneral autoimmune or neurodegenerative disorder, including but notlimited to multiple sclerosis or psoriasis, the method comprising theadministration of a therapeutically effective amount of one or morefumarate esters comprising any one of the pharmaceutical compositionsdescribed herein to a subject in need thereof, wherein the subjectachieves a reduction of annualized relapse rate relative to baselinewithout substantially experiencing one or more of flushing, abdominalpain, diarrhea, and nausea. In another aspect, the endpoint may be lessthan about 2%, about 5%, about 10%, about 15%, about 20%, about 25%,about 30%, about 35%, about 45%, about 50%, or greater than about 50%,relative to baseline.

Endpoints for treating multiple sclerosis using fumarate esters aredescribed in the TECFIDERA® Prescribing Information (Biogen Idec Inc.),and U.S. Patent Application Publication No. US 2014/0163100, each ofwhich is incorporated by reference herein for such teachings. Otherpharmaceutical compositions and methods for treating multiple sclerosisare described in U.S. Pat. Nos. 6,509,376; 7,320,999; 7,619,001;7,803,840; 8,399,514; 8,524,773; and 8,759,393, and International PatentApplication Publication No. WO 2013/119677, each of which isincorporated by reference herein for such teachings.

Another embodiment described herein is a pharmaceutical composition foradministration to a subject with multiple sclerosis or psoriasiscomprising a therapeutically effective amount of one or more fumarateesters, wherein the subject achieves a reduction of annualized relapserate relative to baseline without substantially experiencing one or moreof flushing, abdominal pain, diarrhea, and nausea. In one aspect thereduction of annualized relapse rate may be about 1%, about 2%, about5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%,about 45%, about 50%, or greater than about 50%.

For the treatment of multiple sclerosis (e.g., relapsing forms of MSsuch as RRMS), the dosage form administered to the subject or subject inneed thereof comprises a pharmaceutical composition comprisingmicronized solid particles of a fumarate ester as the only activeingredient or in combination with one or more NSAIDS (e.g., aspirin) orleukotriene receptor antagonists (e.g., montelukast or zafirlukast). Inone aspect, the effective amount of fumarate ester is about 320 mg toabout 460 mg FAE per day and the subjects can receive the effectiveamount, e.g., about 80 mg to about 115 mg FAE quater in die (QID), inthe form of four capsules a day, to be taken orally, including allintegers and fractions within the specified ranges. In another aspect,the effective amount is about 85 mg to about 110 mg FAE quater in die(QID). In another aspect, the effective amount is about 90 mg to about100 mg FAE quater in die (QID). In another aspect, the effective amountis about 90 mg to about 107 mg FAE quater in die (QID). In anotheraspect, the effective amount is about 100 mg to about 108 mg FAE quaterin die (QID). In another aspect, the effective amount is about 105 mg toabout 110 mg FAE quater in die (QID). In one aspect, the effectiveamount of fumarate ester is about 340 mg to about 460 mg FAE per day andthe subjects can receive the effective amount, e.g., about 170 mg toabout 230 mg FAE bis in die (BID), in the form of two capsules a day, tobe taken orally, including all integers and fractions within thespecified ranges. In another aspect, the effective amount is about 205mg to about 230 mg FAE BID. In a further aspect, the effective amount isabout 210 mg to about 220 mg FAE BID. In a further aspect, the effectiveamount is about 210 mg to 216 mg FAE BID. In a further aspect, theeffective amount is about 212 mg to 216 mg FAE BID. In another aspect,the effective amount of FAE is about 340 mg to about 460 mg FAE per dayand the subjects can receive the effective amount, e.g., about 340 toabout 460 mg FAE quaque die (QD), in the form of one capsule a day, tobe taken orally, including all integers and fractions within thespecified ranges.

In another embodiment, for the treatment of multiple sclerosis the dailyeffective amount of FAE is from 80 mg FAE to 85 mg FAE, 80 mg FAE to 90mg FAE, 80 mg FAE to 95 mg FAE, 85 mg FAE to 100 mg FAE, 85 mg FAE to 90mg FAE, 85 mg FAE to 95 mg FAE, 90 mg FAE to 100 mg FAE, 90 mg FAE to105 mg FAE, 90 mg FAE to 95 mg FAE, 95 mg FAE to 100 mg FAE, 95 mg FAEto 105 mg FAE, 95 mg FAE to 110 mg FAE, 100 mg FAE to 105 mg FAE, 100 mgFAE to 110 mg FAE, 100 mg FAE to 115 mg FAE, 105 mg FAE to 110 mg FAE,105 mg FAE to 115 mg FAE, 105 mg FAE to 120 mg FAE, 110 mg FAE to 115 mgFAE, 110 mg FAE to 120 mg FAE, 110 mg FAE to 125 mg FAE, 115 mg FAE to120 mg FAE, 115 mg FAE to 125 mg FAE, 115 mg FAE to 130 mg FAE, 120 mgFAE to 125 mg FAE, 120 mg FAE to 130 mg FAE, 120 mg FAE to 135 mg FAE,125 mg FAE to 130 mg FAE, 125 mg FAE to 135 mg FAE, 125 mg FAE to 140 mgFAE, 130 mg FAE to 135 mg FAE, 130 mg FAE to 140 mg FAE, 130 mg FAE to145 mg FAE, 135 mg FAE to 140 mg FAE, 135 mg FAE to 145 mg FAE, 135 mgFAE to 150 mg FAE, 140 mg FAE to 145 mg FAE, 140 mg FAE to 150 mg FAE,140 mg FAE to 155 mg FAE, 145 mg FAE to 150 mg FAE, 145 mg FAE to 155 mgFAE, 145 mg FAE to 160 mg FAE, 150 mg FAE to 155 mg FAE, 150 mg FAE to160 mg FAE, 150 mg FAE to 165 mg FAE, 155 mg FAE to 160 mg FAE, 155 mgFAE to 165 mg FAE, 155 mg FAE to 170 mg FAE, 160 mg FAE to 165 mg FAE,160 mg FAE to 170 mg FAE, 160 mg FAE to 175 mg FAE, 165 mg FAE to 170 mgFAE, 165 mg FAE to 175 mg FAE, 165 mg FAE to 180 mg FAE, 170 mg FAE to175 mg FAE, 170 mg FAE to 180 mg FAE, 170 mg FAE to 185 mg FAE, 175 mgFAE to 180 mg FAE, 175 mg FAE to 185 mg FAE, 175 mg FAE to 190 mg FAE,180 mg FAE to 185 mg FAE, 180 mg FAE to 190 mg FAE, 180 mg FAE to 195 mgFAE, 185 mg FAE to 190 mg FAE, 185 mg FAE to 195 mg FAE, 185 mg FAE to200 mg FAE, 190 mg FAE to 195 mg FAE, 190 mg FAE to 200 mg FAE, 190 mgFAE to 205 mg FAE, 195 mg FAE to 200 mg FAE, 195 mg FAE to 205 mg FAE,195 mg FAE to 210 mg FAE, 200 mg FAE to 205 mg FAE, 200 mg FAE to 210 mgFAE, 200 mg FAE to 215 mg FAE, 205 mg FAE to 210 mg FAE, 205 mg FAE to215 mg FAE, 205 mg FAE to 220 mg FAE, 210 mg FAE to 215 mg FAE, 210 mgFAE to 220 mg FAE, 210 mg FAE to 225 mg FAE, 215 mg FAE to 220 mg FAE,215 mg FAE to 225 mg FAE, 215 mg FAE to 230 mg FAE, 220 mg FAE to 225 mgFAE, 220 mg FAE to 230 mg FAE, 220 mg FAE to 235 mg FAE, 225 mg FAE to230 mg FAE, 225 mg FAE to 235 mg FAE, 225 mg FAE to 240 mg FAE, 230 mgFAE to 235 mg FAE, 230 mg FAE to 240 mg FAE, 230 mg FAE to 245 mg FAE,235 mg FAE to 240 mg FAE, 235 mg FAE to 245 mg FAE, 235 mg FAE to 250 mgFAE, 240 mg FAE to 245 mg FAE, 240 mg FAE to 250 mg FAE, 240 mg FAE to255 mg FAE, 245 mg FAE to 250 mg FAE, 245 mg FAE to 255 mg FAE, 245 mgFAE to 260 mg FAE, 250 mg FAE to 255 mg FAE, 250 mg FAE to 260 mg FAE,250 mg FAE to 265 mg FAE, 255 mg FAE to 260 mg FAE, 255 mg FAE to 265 mgFAE, 255 mg FAE to 270 mg FAE, 260 mg FAE to 265 mg FAE, 260 mg FAE to270 mg FAE, 260 mg FAE to 275 mg FAE, 265 mg FAE to 270 mg FAE, 265 mgFAE to 275 mg FAE, 265 mg FAE to 280 mg FAE, 270 mg FAE to 275 mg FAE,270 mg FAE to 280 mg FAE, 270 mg FAE to 285 mg FAE, 275 mg FAE to 280 mgFAE, 275 mg FAE to 285 mg FAE, 275 mg FAE to 290 mg FAE, 280 mg FAE to285 mg FAE, 280 mg FAE to 290 mg FAE, 280 mg FAE to 295 mg FAE, 285 mgFAE to 290 mg FAE, 285 mg FAE to 295 mg FAE, 285 mg FAE to 300 mg FAE,290 mg FAE to 295 mg FAE, 290 mg FAE to 300 mg FAE, 290 mg FAE to 305 mgFAE, 295 mg FAE to 300 mg FAE, 295 mg FAE to 305 mg FAE, 295 mg FAE to310 mg FAE, 300 mg FAE to 305 mg FAE, 300 mg FAE to 310 mg FAE, 300 mgFAE to 315 mg FAE, 305 mg FAE to 310 mg FAE, 305 mg FAE to 315 mg FAE,305 mg FAE to 320 mg FAE, 310 mg FAE to 315 mg FAE, 310 mg FAE to 320 mgFAE, 310 mg FAE to 325 mg FAE, 315 mg FAE to 320 mg FAE, 315 mg FAE to325 mg FAE, 315 mg FAE to 330 mg FAE, 320 mg FAE to 325 mg FAE, 320 mgFAE to 330 mg FAE, 320 mg FAE to 335 mg FAE, 325 mg FAE to 330 mg FAE,325 mg FAE to 335 mg FAE, 325 mg FAE to 340 mg FAE, 330 mg FAE to 335 mgFAE, 330 mg FAE to 340 mg FAE, 330 mg FAE to 345 mg FAE, 335 mg FAE to340 mg FAE, 335 mg FAE to 345 mg FAE, 335 mg FAE to 350 mg FAE, 340 mgFAE to 345 mg FAE, 340 mg FAE to 350 mg FAE, 340 mg FAE to 355 mg FAE,345 mg FAE to 350 mg FAE, 345 mg FAE to 355 mg FAE, 345 mg FAE to 360 mgFAE, 350 mg FAE to 355 mg FAE, 350 mg FAE to 360 mg FAE, 350 mg FAE to365 mg FAE, 355 mg FAE to 360 mg FAE, 355 mg FAE to 365 mg FAE, 355 mgFAE to 370 mg FAE, 360 mg FAE to 365 mg FAE, 360 mg FAE to 370 mg FAE,360 mg FAE to 375 mg FAE, 365 mg FAE to 370 mg FAE, 365 mg FAE to 375 mgFAE, 365 mg FAE to 380 mg FAE, 370 mg FAE to 375 mg FAE, 370 mg FAE to380 mg FAE, 370 mg FAE to 385 mg FAE, 375 mg FAE to 380 mg FAE, 375 mgFAE to 385 mg FAE, 375 mg FAE to 390 mg FAE, 380 mg FAE to 385 mg FAE,380 mg FAE to 390 mg FAE, 380 mg FAE to 395 mg FAE, 385 mg FAE to 390 mgFAE, 385 mg FAE to 395 mg FAE, 385 mg FAE to 400 mg FAE, 390 mg FAE to395 mg FAE, 390 mg FAE to 400 mg FAE, 390 mg FAE to 405 mg FAE, 395 mgFAE to 400 mg FAE, 395 mg FAE to 405 mg FAE, 395 mg FAE to 410 mg FAE,400 mg FAE to 405 mg FAE, 400 mg FAE to 410 mg FAE, 400 mg FAE to 415 mgFAE, 405 mg FAE to 410 mg FAE, 405 mg FAE to 415 mg FAE, 405 mg FAE to420 mg FAE, 410 mg FAE to 415 mg FAE, 410 mg FAE to 420 mg FAE, 410 mgFAE to 425 mg FAE, 415 mg FAE to 420 mg FAE, 415 mg FAE to 425 mg FAE,415 mg FAE to 430 mg FAE, 420 mg FAE to 425 mg FAE, 420 mg FAE to 430 mgFAE, 420 mg FAE to 435 mg FAE, 425 mg FAE to 430 mg FAE, 425 mg FAE to435 mg FAE, 425 mg FAE to 440 mg FAE, 430 mg FAE to 435 mg FAE, 430 mgFAE to 440 mg FAE, 430 mg FAE to 445 mg FAE, 435 mg FAE to 440 mg FAE,435 mg FAE to 445 mg FAE, 435 mg FAE to 450 mg FAE, 440 mg FAE to 445 mgFAE, 440 mg FAE to 450 mg FAE, 440 mg FAE to 455 mg FAE, 445 mg FAE to450 mg FAE, 445 mg FAE to 455 mg FAE, 445 mg FAE to 460 mg FAE, 450 mgFAE to 455 mg FAE, 450 mg FAE to 460 mg FAE, 450 mg FAE to 465 mg FAE,455 mg FAE to 460 mg FAE, 455 mg FAE to 465 mg FAE, 455 mg FAE to 470 mgFAE, 460 mg FAE to 465 mg FAE, 460 mg FAE to 470 mg FAE, 460 mg FAE to475 mg FAE, 465 mg FAE to 470 mg FAE, 465 mg FAE to 475 mg FAE, 465 mgFAE to 480 mg FAE, 470 mg FAE to 475 mg FAE, 470 mg FAE to 480 mg FAE,or 475 mg FAE to 480 mg FAE. The effective amount can be administered inone or more doses, once, twice, three, four, or more times per day.

For the treatment of autoimmune disorders, including multiple sclerosisand psoriasis, the dosage form administered to the subject or subject inneed thereof comprises a pharmaceutical composition comprisingmicronized solid particles of a fumarate ester as the only activeingredient. In one embodiment, the effective amount of fumarate ester isabout 340 mg to about 440 mg FAE per day and the subjects can receivethe effective amount, e.g., about 340 mg to about 440 mg FAE per day, inthe form of two dosage forms comprising 85 mg to about 110 mg FAE,simultaneously administered bis in die (BID), fora total of fourcapsules per day to be taken orally (e.g., two capsules administeredante meridiem and two capsules administered post meridiem).

In another embodiment, the effective amount of fumarate ester is about380 mg to about 400 mg FAE per day and the subjects can receive theeffective amount, e.g., about 380 mg to about 400 mg FAE per day, in theform of two dosage forms comprising about 95 mg to about 100 mg FAE,simultaneously administered bis in die (BID), for a total of fourcapsules a day to be taken orally (e.g., two capsules administered antemeridiem and two capsules administered post meridiem). In one aspect,the dosage form comprises about 95 mg FAE. In another aspect, the dosageform comprises 100 mg FAE. In one embodiment, dosing regimen comprisestwo 95 mg dosage forms administered BID for a total of 380 mg FAE perday. In another embodiment, dosing regimen comprises two 100 mg dosageforms administered BID for a total of 400 mg FAE per day.

Without being bound by any theory, it is thought that simultaneouslyadministering two small dosage forms, such as two 95 mg FAE or 100 mgFAE soft capsule dosage forms (e.g., total fill weight of about 250 toabout 300 mg in a 5 oval capsule) provides more rapid gastric emptyingand transit to the duodenum as compared to a single larger dosage form,such as a single 200 mg of FAE soft capsule dosage form (e.g., totalfill weight of about 500 mg to about 600 mg in a 12 oval capsule). Thismay provide a more rapid T_(max) and also reduce C_(max) because of thelower FAE dose. This may also reduce gastrointestinal side effects.

In another embodiment, the effective amount of fumarate ester is about400 mg to about 420 mg FAE per day and the subjects can receive theeffective amount, e.g., about 400 mg to about 420 mg FAE per day, in theform of two dosage forms comprising about 180 mg to about 210 mg in theform of two capsules per day, to be taken orally (e.g., one capsuleadministered ante meridiem and one capsules administered post meridiem).In one aspect, the dosage form comprises 180 mg FAE. In another aspect,the dosage form comprises 190 mg FAE. In one aspect, the dosage formcomprises about 200 mg FAE. In another aspect, the dosage form comprises205 mg FAE. In another aspect, the dosage form comprises 210 mg FAE.

In another embodiment, the effective amount of fumarate ester is about400 mg to about 440 mg FAE per day and the subjects can receive theeffective amount, e.g., about 400 mg to about 440 mg FAE per day, in theform of two dosage forms comprising about 200 mg to about 220 mg in theform of two capsules a day, to be taken orally (e.g., one capsuleadministered ante meridiem and one capsules administered post meridiem).In one aspect, the dosage form comprises about 200 mg FAE. In anotheraspect, the dosage form comprises 210 mg FAE. In another aspect, thedosage form comprises 215 mg FAE. In another aspect, the dosage formcomprises 220 mg FAE.

For the treatment of autoimmune disorders, including multiple sclerosisand psoriasis, the dosage form administered to the subject or subject inneed thereof comprises a pharmaceutical composition comprisingmicronized solid particles of a fumarate ester as the only activeingredient or in combination with one or more NSAIDS (e.g., aspirin) orleukotriene receptor antagonists (e.g., montelukast or zafirlukast). Inone aspect, the effective amount of fumarate ester is about 340 mg toabout 440 mg FAE per day and the subjects can receive the effectiveamount, e.g., about 85 mg to about 110 mg FAE quater in die (QID), inthe form of four capsules a day, to be taken orally, including allintegers and fractions within the specified ranges. In one aspect, theeffective amount of fumarate ester is about 340 mg to about 440 mg FAEper day and the subjects can receive the effective amount, e.g., about170 mg to about 220 mg FAE bis in die (BID), in the form of two capsulesa day, to be taken orally, including all integers and fractions withinthe specified ranges. In another aspect, the effective amount offumarate ester is about 340 mg to about 440 mg FAE per day and thesubjects can receive the effective amount, e.g., about 340 mg to about440 mg FAE quaque die (QD), in the form of one capsule a day, to betaken orally, including all integers and fractions within the specifiedranges.

Fumarate esters can cause flushing and gastrointestinal (GI) sideeffects in some subjects. While the side effects generally subside soonafter subjects start on the treatment, in one aspect the starting doseis about 85 mg to about 110 mg FAE BID orally for the first 7 days,including all integers and fractions within the specified range. Thedose is increased to the effective dose of about 170 mg to about 220 mgFAE BID (e.g., about 340 mg to about 440 mg FAE per day), including allintegers and fractions within the specified ranges. In another aspect,the starting dose is about 170 mg to about 220 mg FAE BID orally for thefirst 7 days, including all integers and fractions within the specifiedranges. The dose is increased to the effective dose of about 340 mg toabout 440 mg FAE QD (e.g., about 340 mg to about 440 mg FAE per day),including all integers and fractions within the specified ranges. Forthose subjects who experience GI or flushing side effects, taking FAEwith food can improve tolerability. In one aspect described herein, FAEis administered after a meal. In another aspect described herein, FAE isadministered after a high-fat meal to reduce or ameliorate the one ormore symptoms of flushing, abdominal pain, diarrhea, and nausea in thesubject.

In one embodiment, the pharmaceutical compositions described herein canbe administered without titration of the pharmaceutical composition. Inone aspect, the pharmaceutical compositions can be administered withouttitration and without substantially inducing one or more side effectsincluding, but not limited to flushing, abdominal pain, diarrhea, ornausea.

In one embodiment, the pharmaceutical composition described herein doesnot elicit the flushing and gastrointestinal side effects when the doseis about 85 mg to about 110 mg FAE quater in die (QID) or two dosessimultaneously bis in die (BID) (e.g., 340 mg to about 440 mg FAE perday), including all integers and fractions within the specified ranges.In another embodiment, the pharmaceutical composition described hereindoes not elicit the flushing and gastrointestinal side effects when thedose is about 170 mg to about 220 mg FAE bis in die (BID) (e.g., 340 mgto about 440 mg FAE per day), including all integers and fractionswithin the specified ranges. In one embodiment, the pharmaceuticalcomposition described herein does not elicit the flushing andgastrointestinal side effects when the dose is about 340 mg to about 440mg FAE quaque die (QD) (e.g., 340 mg to about 440 mg FAE per day),including all integers and fractions within the specified ranges.

In one embodiment, the pharmaceutical composition described herein doesnot elicit flushing and gastrointestinal side effects when the effectiveamount is about 180 mg FAE quaque die (QD) (e.g., 180 mg FAE per day).In another embodiment, the pharmaceutical composition described hereindoes not elicit the flushing and gastrointestinal side effects when theeffective amount is about 170 mg to about 220 mg FAE quaque die (QD)(e.g., 170 mg to about 220 mg FAE per day), including all integers andfractions within the specified ranges. In another embodiment, thepharmaceutical composition described herein does not elicit the flushingand gastrointestinal side effects when the effective amount is about 340mg to about 440 mg FAE quaque die (QD) (e.g., 340 mg to about 440 mg FAEper day), including all integers and fractions within the specifiedranges.

In one embodiment described herein, without being bound to any theory,it is surprising and unexpected that the pharmaceutical compositionsdescribed herein comprising liquid dosage forms of FAE provide effectivetreatment of multiple sclerosis at total daily dosages of about 380 mgFAE to about 400 mg FAE when compared to a total daily dosage of 480 mgdimethyl fumarate administered as TECFIDERA®. In one embodimentdescribed herein, the FAE is DMF. In another embodiment describedherein, the FAE is monomethyl fumarate. In another embodiment describedherein, the FAE is DMF, MMF, other MMF prodrug, or a combinationthereof.

In another aspect, the administration of about 325 mg of non-entericcoated aspirin 30-minutes prior to FAE dosing can reduce the occurrenceand severity of flushing. In one aspect, subjects who experienceflushing with gastrointestinal side effects may reduce the dose to about100 mg to about 120 mg FAE BID temporarily, including all integers andfractions within the specified range. Within a month, the effective doseof about 170 mg to about 220 mg FAE BID should be resumed, including allintegers and fractions within the specified range. In another aspect,subjects who experience flushing with gastrointestinal side effects mayreduce the dose to about 170 mg to about 220 mg FAE BID temporarily,including all integers and fractions within the specified range. Withina month, the effective dose of about 340 mg to about 440 mg FAE QDshould be resumed, including all integers and fractions within thespecified range.

In one embodiment, a subject administered a FAE pharmaceuticalcomposition described herein may take one or more non-steroidalanti-inflammatory drugs (NSAID) before (for example, about 10 minutes toan hour, e.g., about 30 minutes before) taking a FAE pharmaceuticalcomposition described herein. In one embodiment, the subjectadministered a dosage form takes the one or more non-steroidalanti-inflammatory drugs to reduce flushing. In one embodiment, the oneor more non-steroidal anti-inflammatory drugs comprise aspirin,ibuprofen, naproxen, ketoprofen, celecoxib, or combinations thereof. Theone or more non-steroidal anti-inflammatory drugs can be administered inan amount of about 50 mg to about 500 mg before taking the dosage formdescribed herein. In one embodiment, a subject takes 325 mg aspirinabout 30-minutes before taking the dosage forms described herein.

In another embodiment, a subject administered a FAE pharmaceuticalcomposition described herein may take one or more leukotriene receptorantagonists. In another embodiment, a subject administered a FAEpharmaceutical composition described herein may take 10 to 20 mg ofmontelukast (Singulair®) or zafirlukast (Accolate®).

In another embodiment described herein, subjects are orally administeredone or more non-steroidal anti-inflammatory drugs before taking thedosage form described herein exhibit the same pharmacokinetic properties(e.g., C_(max) and AUC) as subjects orally administered the dosage formdescribed herein without administering one or more non-steroidalanti-inflammatory drugs (e.g., aspirin, ibuprofen, naproxen, ketoprofen,celecoxib, or combinations thereof). The NSAID can be administered about30-minutes before taking the dosage form described herein.

In one embodiment described herein, a subject is administered one ormore dosage forms containing about 80 mg to about 460 mg FAE, one ormore times daily for a total daily dose of about 320 mg to about 460 mg,including all integers and fractions within the specified range. In oneaspect, the pharmaceutical composition comprises an immediate release,delayed release, controlled release, or extended release formulation ofa fumarate ester. In one embodiment, the matrix is a controlled releasematrix. In another embodiment, the matrix is a delayed release matrix.In another embodiment, the matrix is an extended release matrix. Inanother aspect, the pharmaceutical composition comprises a soft capsule.In another aspect, the pharmaceutical composition comprises a softcapsule comprising one or more subcoatings, top coatings, entericcoatings, or combinations thereof.

In one embodiment, subjects having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, are administered one or more dosage formscomprising about 80 mg to about 110 mg FAE, twice-daily for a totaldaily dose of about 320 mg to about 440 mg, wherein the dosage formcomprises solid microparticles of FAE in a liquid matrix. In oneembodiment, the matrix is a controlled release matrix.

In one embodiment, subjects having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, are administered one or more dosage formscomprising about 95 mg to about 100 mg FAE, twice-daily for a totaldaily dose of about 190 mg to about 200 mg, wherein the dosage formscomprise solid microparticles of FAE suspended in a liquid matrix. Inone embodiment, the matrix is a controlled release matrix.

In one embodiment, subjects having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, are simultaneously administered two dosage formscomprising about 95 mg to about 100 mg FAE, twice-daily for a totaldaily dose of about 380 mg to about 400 mg, wherein the soft capsulecomprises solid microparticles of FAE suspended in a liquid matrix. Inone embodiment, the matrix is a controlled release matrix.

In one embodiment, subjects having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, are administered a dosage form containing about200 mg FAE, twice daily for a total daily dose of about 400 mg, whereinthe dosage form comprises solid microparticles of FAE suspended in amatrix. In one embodiment, the matrix is a controlled release matrix.

Pharmacokinetics of fumarate esters, particularly DMF, are described bySheikh et al., Clinical Therapeutics 35(10): 1582-1594 (2013), which isincorporated by reference herein for such teachings. After oraladministration of dimethyl fumarate, the molecule undergoes rapidpresystemic hydrolysis by esterases and is converted to the activemetabolite, monomethyl fumarate (MMF). Dimethyl fumarate is notquantifiable in plasma following oral administration. Allpharmacokinetic analyses related to DMF are performed with plasma MMFconcentrations. When monomethyl fumarate is orally administered, the MMFmolecule concentration can be directly measured in plasma.

In one embodiment, the pharmaceutical composition described herein isprovided in a dosage form containing a total amount of about 85 mg toabout 110 mg of a fumarate ester, wherein subjects administered the doseexhibit a mean plasma monomethyl fumarate C_(max) ranging from about 0.2mg/L to about 2.41 mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 85 mg to about 110 mg ofa fumarate ester, wherein subjects administered the dose exhibit a meanplasma monomethyl fumarate C_(max) ranging from about 0.4 mg/L to about2.41 mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose exhibit a mean plasmamonomethyl fumarate C_(max) ranging from about 1.5 mg/L to about 3.4mg/L, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose exhibit a mean plasmamonomethyl fumarate C_(max) ranging from about 1.03 mg/L to about 2.41mg/L, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose exhibit a mean plasmamonomethyl fumarate C_(max) ranging from about 0.4 mg/L to about 0.75mg/L, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose exhibit a mean plasmamonomethyl fumarate C_(max) ranging from about 0.76 mg/L to about 1.03mg/L, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose exhibit a mean plasmamonomethyl fumarate C_(max) ranging from about 1.04 mg/L to about 1.75mg/L, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose exhibit a mean plasmamonomethyl fumarate C_(max) ranging from about 1.75 mg/L to about 2.41mg/L, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose exhibit a mean plasmamonomethyl fumarate C_(max) of at least 0.4 mg/L, at least 0.5 mg/L, atleast 0.6 mg/L, at least 0.7 mg/L, at least 0.8 mg/L, at least 0.9 mg/L,at least 1 mg/L, at least 1.1 mg/L, at least 1.2 mg/L, at least 1.3mg/L, at least 1.4 mg/L, at least 1.5 mg/L, at least 1.6 mg/L, at least1.7 mg/L, at least 1.8 mg/L, at least 1.9 mg/L, at least 2 mg/L, atleast 2.1 mg/L, at least 2.2 mg/L, at least 2.3 mg/L, at least 2.4 mg/L,at least 2.5 mg/L, at least 2.6 mg/L, at least 2.7 mg/L, at least 2.8mg/L, at least 2.9 mg/L, at least 3 mg/L, at least 3.1 mg/L, at least3.2 mg/L, at least 3.3 mg/L, or at least 3.4 mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose form four times dailyexhibit a mean plasma monomethyl fumarate AUC_(overall) ranging fromabout 1.0 h·mg/L to about 15.2 h·mg/L, including all integers andfractions within the specified ranges. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 85 mg to about 110 mg of a fumarate ester, wherein subjectsadministered the dose form four times daily exhibit a mean plasmamonomethyl fumarate AUC_(overall) ranging from about 2.01 h·mg/L toabout 5.2 h·mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 85 mg to about 110 mg ofa fumarate ester, wherein subjects administered the dose form four timesdaily exhibit a mean plasma monomethyl fumarate AUC_(overall) rangingfrom about 1.0 h·mg/L to about 5.2 h·mg/L, including all integers andfractions within the specified ranges. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 85 mg to about 110 mg of a fumarate ester, wherein subjectsadministered the dose form four times daily exhibit a mean plasmamonomethyl fumarate AUC_(overall) ranging from about 11.3 h·mg/L toabout 15.2 h·mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 85 mg to about 110 mg ofa fumarate ester, wherein subjects administered the dose form four timesdaily exhibit a mean plasma monomethyl fumarate AUC_(overall) rangingfrom about 3.2 h·mg/L to about 11.2 h·mg/L, including all integers andfractions within the specified ranges. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 85 mg to about 110 mg of a fumarate ester, wherein subjectsadministered the dose form four times daily exhibit a mean plasmamonomethyl fumarate AUC_(overall) ranging from about 5.2 h·mg/L to about11.2 h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose form four times dailyexhibit a mean plasma monomethyl fumarate AUC_(overall) at least about1.0 h·mg/L, at least 1.2 h·mg/L, at least 1.4 h·mg/L, at least 1.6h·mg/L, at least 1.8 h·mg/L, at least 2.0 h·mg/L, at least 2.3 h·mg/L,at least about 2.6 h·mg/L, at least about 2.9 h·mg/L, at least 3.2h·mg/L, at least 3.5 h·mg/L, at least 3.8 h·mg/L, at least 4.1 h·mg/L,at least 4.4 h·mg/L, at least 4.7 h·mg/L, at least 5.0 h·mg/L, at least5.3 h·mg/L, at least 5.6 h·mg/L, at least 5.9 h·mg/L, at least 6.2h·mg/L, at least 6.5 h·mg/L, at least 6.8 h·mg/L, at least 7.1 h·mg/L,at least 7.4 h·mg/L, at least 7.7 h·mg/L, at least 8.0 h·mg/L, at least8.3 h·mg/L, at least 8.6 h·mg/L, at least 8.9 h·mg/L, at least 9.2h·mg/L, at least 9.5 h·mg/L, at least 9.8 h·mg/L, at least 10.1 h·mg/L,at least 10.4·h·mg/L, at least 10.7 h·mg/L, at least 11.0 h·mg/L, atleast 11.3 h·mg/L, at least 11.6 h·mg/L, at least 11.9 h·mg/L, at least12.2 h·mg/L, at least 12.5 h·mg/L, at least 12.8 h·mg/L, at least 13.1h·mg/L, at least 13.3 h·mg/L, at least 13.6 h·mg/L, at least 13.9h·mg/L, at least 14.2 h·mg/L, at least 14.5 h·mg/L, at least 14.8h·mg/L, or at least 15.2 h·mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate AUC_(0→12 h) ranging from about 0.5 h·mg/L to about5.5 h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate AUC_(0→12 h) ranging from about 0.5 h·mg/L to about2.5 h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate AUC_(0→12 h) ranging from about 2.6 h·mg/L to about5.5 h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate AUC_(0→12 h) of at least about 0.5 h·mg/L, at least1.0 h·mg/L, at least 1.2 h·mg/L, at least 1.4 h·mg/L, at least 1.6h·mg/L, at least 1.8 h·mg/L, at least 2.0 h·mg/L, at least 2.1 h·mg/L,at least 2.2 h·mg/L, at least 2.3 h·mg/L, at least 2.4 h·mg/L, at least2.5 h·mg/L, at least 2.6 h·mg/L, at least 2.7 h·mg/L, at least 2.8h·mg/L, at least 2.9 h·mg/L, at least 3 h·mg/L, at least 3.1 h·mg/L, atleast 3.2 h·mg/L, at least 3.3 h·mg/L, at least 3.4 h·mg/L, at least 3.5h·mg/L, at least 3.6 h·mg/L, at least 3.7 h·mg/L, at least 3.8 h·mg/L,at least 3.9 h·mg/L, at least 4 h·mg/L, at least 4.1 h·mg/L, at least4.2 h·mg/L, at least 4.3 h·mg/L, at least 4.4 h·mg/L, at least 4.5h·mg/L, at least 4.6 h·mg/L, at least 4.7 h·mg/L, at least 4.8 h·mg/L,at least 4.9 h·mg/L, at least 5 h·mg/L, at least 5.1 h·mg/L, at least5.2 h·mg/L, at least 5.3 h·mg/L, at least 5.4 h·mg/L, or at least 5.5h·mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate AUC_(0→∞) ranging from about 0.5 h·mg/L to about 5.6h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate AUC_(0→∞) ranging from about 0.5 h·mg/L to about 2.6h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate AUC_(0→∞) ranging from about 2.6 h·mg/L to about 5.5h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate AUC_(0→∞) of at least about 0.5 h·mg/L, at least 1.0h·mg/L, at least 1.2 h·mg/L, at least 1.4 h·mg/L, at least 1.6 h·mg/L,at least 1.8 h·mg/L, at least 2 h·mg/L, at least 2.1 h·mg/L, at least2.2 h·mg/L, at least 2.3 h·mg/L, at least 2.4 h·mg/L, at least 2.5h·mg/L, at least 2.6 h·mg/L, at least 2.7 h·mg/L, at least 2.8 h·mg/L,at least 2.9 h·mg/L, at least 3 h·mg/L, at least 3.1 h·mg/L, at least3.2 h·mg/L, at least 3.3 h·mg/L, at least 3.4 h·mg/L, at least 3.5h·mg/L, at least 3.6 h·mg/L, at least 3.7 h·mg/L, at least 3.8 h·mg/L,at least 3.9 h·mg/L, at least 4 h·mg/L, at least 4.1 h·mg/L, at least4.2 h·mg/L, at least 4.3 h·mg/L, at least 4.4 h·mg/L, at least 4.5h·mg/L, at least 4.6 h·mg/L, at least 4.7 h·mg/L, at least 4.8 h·mg/L,at least 4.9 h·mg/L, at least 5 h·mg/L, at least 5.1 h·mg/L, at least5.2 h·mg/L, at least 5.3 h·mg/L, at least 5.4 h·mg/L, or at least 5.5h·mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate T_(max) ranging from about 1.5 hours to about 8.5hours, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate T_(max) ranging from about 1.6 hours to about 2.5hours, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate T_(max) ranging from about 2.6 hours to about 5hours, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate T_(max) ranging from about 5.1 hours to about 7.5hours, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 85 mg to about 110 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate T_(max) ranging from about 7.6 hours to about 8.5hours, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 240 mg to about 240 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate T_(max) of at least 1.6 hours, at least 1.8 hours,at least 2 hours, at least 2.2 hours, at least 2.4 hours, at least 2.6hours, at least 2.8 hours, at least 3 hours, at least 3.2 hours, atleast 3.4 hours, at least 3.6 hours, at least 3.8 hours, at least 4hours, at least 4.2 hours, at least 4.4 hours, at least 4.6 hours, atleast 4.8 hours, at least 5 hours, at least 5.2 hours, at least 5.4hours, at least 5.6 hours, at least 5.8 hours, at least 6 hours, atleast 6.2 hours, at least 6.4 hours, at least 6.6 hours, at least 6.8hours, at least 7 hours, at least 7.2 hours, at least 7.4 hours, atleast 7.6 hours, at least 7.8 hours, at least 8 hours, at least 8.2hours, or at least 8.4 hours.

In one embodiment described herein, a subject is administered a capsulecontaining about 170 mg to about 220 mg FAE, twice daily for a totaldaily dose of about 340 mg to about 440 mg, including all integers andfractions within the specified range. In one aspect, the pharmaceuticalcomposition comprises an immediate release, delayed release, controlledrelease, or extended release formulation of a fumarate ester. In anotheraspect, the pharmaceutical composition comprises a soft capsule.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate C_(max) ranging from about 0.4 mg/L to about 2.41mg/L, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate C_(max) ranging from about 1.0 mg/L to about 3.4mg/L, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate C_(max) ranging from about 1.03 mg/L to about 2.41mg/L, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate C_(max) ranging from about 0.4 mg/L to about 0.75mg/L, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate C_(max) ranging from about 0.76 mg/L to about 1.03mg/L, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate C_(max) ranging from about 1.04 mg/L to about 1.75mg/L, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate C_(max) ranging from about 1.75 mg/L to about 2.41mg/L, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate C_(max) of at least 0.4 mg/L, at least 0.5 mg/L, atleast 0.6 mg/L, at least 0.7 mg/L, at least 0.8 mg/L, at least 0.9 mg/L,at least 1 mg/L, at least 1.1 mg/L, at least 1.2 mg/L, at least 1.3mg/L, at least 1.4 mg/L, at least 1.5 mg/L, at least 1.6 mg/L, at least1.7 mg/L, at least 1.8 mg/L, at least 1.9 mg/L, at least 2 mg/L, atleast 2.1 mg/L, at least 2.2 mg/L, at least 2.3 mg/L, at least 2.4 mg/L,at least 2.5 mg/L, at least 2.6 mg/L, at least 2.7 mg/L, at least 2.8mg/L, at least 2.9 mg/L, at least 3 mg/L, at least 3.1 mg/L, at least3.2 mg/L, at least 3.3 mg/L, or at least 3.4 mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form twice-daily exhibit amean plasma monomethyl fumarate AUC_(overall) ranging from about 1.0h·mg/L to about 15.2 h·mg/L, including all integers and fractions withinthe specified ranges. In another aspect, the composition is provided ina dosage form containing a total amount of about 170 mg to about 220 mgof a fumarate ester, wherein subjects administered the dose formtwice-daily exhibit a mean plasma monomethyl fumarate AUC_(overall)ranging from about 2.01 h·mg/L to about 5.2 h·mg/L, including allintegers and fractions within the specified ranges. In another aspect,the composition is provided in a dosage form containing a total amountof about 170 mg to about 220 mg of a fumarate ester, wherein subjectsadministered the dose form twice-daily exhibit a mean plasma monomethylfumarate AUC_(overall) ranging from about 1.0 h·mg/L to about 5.2h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form twice-daily exhibit amean plasma monomethyl fumarate AUC_(overall) ranging from about 11.3h·mg/L to about 15.2 h·mg/L, including all integers and fractions withinthe specified ranges. In another aspect, the composition is provided ina dosage form containing a total amount of about 170 mg to about 220 mgof a fumarate ester, wherein subjects administered the dose formtwice-daily exhibit a mean plasma monomethyl fumarate AUC_(overall)ranging from about 4.8 h·mg/L to about 11.2 h·mg/L, including allintegers and fractions within the specified ranges. In another aspect,the composition is provided in a dosage form containing a total amountof about 170 mg to about 220 mg of a fumarate ester, wherein subjectsadministered the dose form twice-daily exhibit a mean plasma monomethylfumarate AUC_(overall) at least about 1.0 h·mg/L, at least 1.2 h·mg/L,at least 1.4 h·mg/L, at least 1.6 h·mg/L, at least 1.8 h·mg/L, at least2.0 h·mg/L, at least 2.3 h·mg/L, at least about 2.6 h·mg/L, at leastabout 2.9 h·mg/L, at least 3.2 h·mg/L, at least 3.5 h·mg/L, at least 3.8h·mg/L, at least 4.1 h·mg/L, at least 4.4 h·mg/L, at least 4.7 h·mg/L,at least 5.0 h·mg/L, at least 5.3 h·mg/L, at least 5.6 h·mg/L, at least5.9 h·mg/L, at least 6.2 h·mg/L, at least 6.5 h·mg/L, at least 6.8h·mg/L, at least 7.1 h·mg/L, at least 7.4 h·mg/L, at least 7.7 h·mg/L,at least 8.0 h·mg/L, at least 8.3 h·mg/L, at least 8.6 h·mg/L, at least8.9 h·mg/L, at least 9.2 h·mg/L, at least 9.5 h·mg/L, at least 9.8h·mg/L, at least 10.1 h·mg/L, at least 10.4·h·mg/L, at least 10.7h·mg/L, at least 11.0 h·mg/L, at least 11.3 h·mg/L, at least 11.6h·mg/L, at least 11.9 h·mg/L, at least 12.2 h·mg/L, at least 12.5h·mg/L, at least 12.8 h·mg/L, at least 13.1 h·mg/L, at least 13.3h·mg/L, at least 13.6 h·mg/L, at least 13.9 h·mg/L, at least 14.2h·mg/L, at least 14.5 h·mg/L, at least 14.8 h·mg/L, or at least 15.2h·mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate AUC_(0→12 h) ranging from about 1.0 h·mg/L to about5.5 h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate AUC_(0→12 h) ranging from about 1.0 h·mg/L to about2.5 h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate AUC_(0→12 h) ranging from about 2.6 h·mg/L to about5.5 h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate AUC_(0→12 h) of at least about 1.0 h·mg/L, at least1.2 h·mg/L, at least 1.4 h·mg/L, at least 1.6 h·mg/L, at least 1.8h·mg/L, at least 2.0 h·mg/L, at least 2.1 h·mg/L, at least 2.2 h·mg/L,at least 2.3 h·mg/L, at least 2.4 h·mg/L, at least 2.5 h·mg/L, at least2.6 h·mg/L, at least 2.7 h·mg/L, at least 2.8 h·mg/L, at least 2.9h·mg/L, at least 3 h·mg/L, at least 3.1 h·mg/L, at least 3.2 h·mg/L, atleast 3.3 h·mg/L, at least 3.4 h·mg/L, at least 3.5 h·mg/L, at least 3.6h·mg/L, at least 3.7 h·mg/L, at least 3.8 h·mg/L, at least 3.9 h·mg/L,at least 4 h·mg/L, at least 4.1 h·mg/L, at least 4.2 h·mg/L, at least4.3 h·mg/L, at least 4.4 h·mg/L, at least 4.5 h·mg/L, at least 4.6h·mg/L, at least 4.7 h·mg/L, at least 4.8 h·mg/L, at least 4.9 h·mg/L,at least 5 h·mg/L, at least 5.1 h·mg/L, at least 5.2 h·mg/L, at least5.3 h·mg/L, at least 5.4 h·mg/L, or at least 5.5 h·mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate AUC_(0→∞) ranging from about 1.0 h·mg/L to about 5.6h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate AUC_(0→∞) ranging from about 1.0 h·mg/L to about 2.5h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate AUC_(0→∞) ranging from about 2.6 h·mg/L to about 5.5h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate AUC_(0→∞) of at least about 1.0 h·mg/L, at least 1.2h·mg/L, at least 1.4 h·mg/L, at least 1.6 h·mg/L, at least 1.8 h·mg/L,at least 2 h·mg/L, at least 2.1 h·mg/L, at least 2.2 h·mg/L, at least2.3 h·mg/L, at least 2.4 h·mg/L, at least 2.5 h·mg/L, at least 2.6h·mg/L, at least 2.7 h·mg/L, at least 2.8 h·mg/L, at least 2.9 h·mg/L,at least 3 h·mg/L, at least 3.1 h·mg/L, at least 3.2 h·mg/L, at least3.3 h·mg/L, at least 3.4 h·mg/L, at least 3.5 h·mg/L, at least 3.6h·mg/L, at least 3.7 h·mg/L, at least 3.8 h·mg/L, at least 3.9 h·mg/L,at least 4 h·mg/L, at least 4.1 h·mg/L, at least 4.2 h·mg/L, at least4.3 h·mg/L, at least 4.4 h·mg/L, at least 4.5 h·mg/L, at least 4.6h·mg/L, at least 4.7 h·mg/L, at least 4.8 h·mg/L, at least 4.9 h·mg/L,at least 5 h·mg/L, at least 5.1 h·mg/L, at least 5.2 h·mg/L, at least5.3 h·mg/L, at least 5.4 h·mg/L, at least 5.5 h·mg/L, or at least 5.6h·mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate T_(max) ranging from about 1.5 hours to about 8.5hours, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate T_(max) ranging from about 1.6 hours to about 2.5hours, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate T_(max) ranging from about 2.6 hours to about 5hours, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate T_(max) ranging from about 5.1 hours to about 7.5hours, including all integers and fractions within the specified ranges.In another aspect, the composition is provided in a dosage formcontaining a total amount of about 170 mg to about 220 mg of a fumarateester, wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate T_(max) ranging from about 7.6 hours to about 8.5hours, including all integers and fractions within the specified ranges.In oner aspect, the composition is provided in a dosage form containinga total amount of about 170 mg to about 220 mg of a fumarate ester,wherein subjects administered the dose form exhibit a mean plasmamonomethyl fumarate T_(max) of at least 1.6 hours, at least 1.8 hours,at least 2 hours, at least 2.2 hours, at least 2.4 hours, at least 2.6hours, at least 2.8 hours, at least 3 hours, at least 3.2 hours, atleast 3.4 hours, at least 3.6 hours, at least 3.8 hours, at least 4hours, at least 4.2 hours, at least 4.4 hours, at least 4.6 hours, atleast 4.8 hours, at least 5 hours, at least 5.2 hours, at least 5.4hours, at least 5.6 hours, at least 5.8 hours, at least 6 hours, atleast 6.2 hours, at least 6.4 hours, at least 6.6 hours, at least 6.8hours, at least 7 hours, at least 7.2 hours, at least 7.4 hours, atleast 7.6 hours, at least 7.8 hours, at least 8 hours, at least 8.2hours, or at least 8.4 hours.

In one embodiment described herein, a subject is administered a capsulecontaining about 340 mg to about 440 mg FAE, once daily for a totaldaily dose of about 340 mg to about 440 mg, including all integers andfractions within the specified ranges. In one aspect, the pharmaceuticalcomposition comprises an immediate release, delayed release, controlledrelease, or extended release formulation of a fumarate ester. In anotheraspect, the pharmaceutical composition comprises a soft capsule. Inanother aspect, the composition is provided in a dosage form containinga total amount of about 340 mg to about 440 mg of a fumarate ester,wherein subjects administered the dose form once daily exhibit a meanplasma monomethyl fumarate C_(max) ranging from about 0.4 mg/L to about5.2 mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 340 mg to about 440 mg of a fumarateester, wherein subjects administered the dose form once daily exhibit amean plasma monomethyl fumarate C_(max) ranging from about 1.5 mg/L toabout 5.2 mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 340 mg to about 440 mg ofa fumarate ester, wherein subjects administered the dose form once dailyexhibit a mean plasma monomethyl fumarate C_(max) ranging from about 0.4mg/L to about 0.75 mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 340 mg to about 440 mg ofa fumarate ester, wherein subjects administered the dose form once dailyexhibit a mean plasma monomethyl fumarate C_(max) ranging from about0.76 mg/L to about 1.03 mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 340 mg toabout 440 mg of a fumarate ester, wherein subjects administered the doseform once daily exhibit a mean plasma monomethyl fumarate C_(max)ranging from about 1.04 mg/L to about 1.75 mg/L, including all integersand fractions within the specified ranges. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 340 mg to about 440 mg of a fumarate ester, wherein subjectsadministered the dose form once daily exhibit a mean plasma monomethylfumarate C_(max) ranging from about 1.75 mg/L to about 2.41 mg/L,including all integers and fractions within the specified ranges. Inanother aspect, the composition is provided in a dosage form containinga total amount of about 340 mg to about 440 mg of a fumarate ester,wherein subjects administered the dose form once daily exhibit a meanplasma monomethyl fumarate C_(max) ranging from about 2.42 mg/L to about3.5 mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 340 mg to about 440 mg of a fumarateester, wherein subjects administered the dose form once daily exhibit amean plasma monomethyl fumarate C_(max) ranging from about 3.6 mg/L toabout 5.2 mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 340 mg to about 440 mg ofa fumarate ester, wherein subjects administered the dose form once dailyexhibit a mean plasma monomethyl fumarate C_(max) of at least about 1.0mg/L, at least 1.1 mg/L, at least 1.2 mg/L, at least 1.3 mg/L, at least1.4 mg/L, at least 1.5 mg/L, at least 1.6 mg/L, at least 1.7 mg/L, atleast 1.8 mg/L, at least 1.9 mg/L, at least 2.0 mg/L, at least 2.1 mg/L,at least 2.2 mg/L, at least 2.3 mg/L, at least 2.4 mg/L, at least 2.5mg/L, at least 2.6 mg/L, at least 2.7 mg/L, at least 2.8 mg/L, at least2.9 mg/L, at least 3.0 mg/L, at least 3.1 mg/L, at least 3.2 mg/L, atleast 3.3 mg/L, at least 3.4 mg/L, at least 3.5 mg/L, at least 3.6 mg/L,at least 3.7 mg/L, at least 3.8 mg/L, at least 3.9 mg/L, at least 4.0mg/L, at least 4.1 mg/L, at least 4.2 mg/L, at least 4.3 mg/L, at least4.4 mg/L, at least 4.5 mg/L, at least 4.6 mg/L, at least 4.7 mg/L, atleast 4.8 mg/L, at least 4.9 mg/L, at least 5.0 mg/L, or at least 5.1mg/L

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 340 mg to about 440 mg of a fumarateester, wherein subjects administered the dose form once daily exhibit amean plasma monomethyl fumarate AUC_(0→12 h) ranging from about 1.0h·mg/L to about 15.5 h·mg/L, including all integers and fractions withinthe specified ranges. In another aspect, the composition is provided ina dosage form containing a total amount of about 340 mg to about 440 mgof a fumarate ester, wherein subjects administered the dose form oncedaily exhibit a mean plasma monomethyl fumarate AUC_(0→12 h) rangingfrom about 1.0 h·mg/L to about 2.5 h·mg/L, including all integers andfractions within the specified ranges. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 340 mg to about 440 mg of a fumarate ester, wherein subjectsadministered the dose form once daily exhibit a mean plasma monomethylfumarate AUC_(0→12 h) ranging from about 2.6 h·mg/L to about 5.5 h·mg/L,including all integers and fractions within the specified ranges. Inanother aspect, the composition is provided in a dosage form containinga total amount of about 340 mg to about 440 mg of a fumarate ester,wherein subjects administered the dose form once daily exhibit a meanplasma monomethyl fumarate AUC_(0→12 h) ranging from about 5.6 h·mg/L toabout 7.5 h·mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 340 mg to about 440 mg ofa fumarate ester, wherein subjects administered the dose form once dailyexhibit a mean plasma monomethyl fumarate AUC_(0→12 h) ranging fromabout 7.6 h·mg/L to about 10.5 h·mg/L, including all integers andfractions within the specified ranges. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 340 mg to about 440 mg of a fumarate ester, wherein subjectsadministered the dose form once daily exhibit a mean plasma monomethylfumarate AUC_(0→12 h) ranging from about 10.5 h·mg/L to about 15.5h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 340 mg to about 440 mg of a fumarateester, wherein subjects administered the dose form once daily exhibit amean plasma monomethyl fumarate AUC_(0→12 h) of at least about 1.0h·mg/L, at least 1.2 h·mg/L, at least 1.4 h·mg/L, at least 1.6 h·mg/L,at least 1.8 h·mg/L, at least 2.0 h·mg/L, at least 2.3 h·mg/L, at least2.6 h·mg/L, at least 2.9 h·mg/L, at least 3.2 h·mg/L, at least 3.5h·mg/L, at least 3.8 h·mg/L, at least 4.1 h·mg/L, at least 4.4 h·mg/L,at least 4.7 h·mg/L, at least 5 h·mg/L, at least 5.3 h·mg/L, at least5.6 h·mg/L, at least 5.9 h·mg/L, at least 6.2 h·mg/L, at least 6.5h·mg/L, at least 6.8 h·mg/L, at least 7.1 h·mg/L, at least 7.4 h·mg/L,at least 7.7 h·mg/L, at least 8.0 h·mg/L, at least 8.3 h·mg/L, at least8.6 h·mg/L, at least 8.9 h·mg/L, at least 9.2 h·mg/L, at least 9.5h·mg/L, at least 9.8 h·mg/L, at least 10.1 h·mg/L, at least 10.4 h·mg/L,at least 10.7 h·mg/L, at least 11.0 h·mg/L, at least 11.3 h·mg/L, atleast 11.6 h·mg/L, at least 11.9 h·mg/L, at least 12.2 h·mg/L, at least12.5 h·mg/L, at least 12.8 h·mg/L, at least 13.1 h·mg/L, at least 13.4h·mg/L, at least 13.7 h·mg/L, at least 14 h·mg/L, at least 14.3 h·mg/L,at least 14.6 h·mg/L, at least 14.9 h·mg/L, at least 15.2 h·mg/L, or atleast 15.5 h·mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 340 mg to about 440 mg of a fumarateester, wherein subjects administered the dose form once daily exhibit amean plasma monomethyl fumarate AUC_(0→∞) ranging from about 1.0 h·mg/Lto about 15.5 h·mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 340 mg to about 440 mg ofa fumarate ester, wherein subjects administered the dose form once dailyexhibit a mean plasma monomethyl fumarate AUC_(0→∞) ranging from about1.5 h·mg/L to about 2.5 h·mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 340 mg toabout 440 mg of a fumarate ester, wherein subjects administered the doseform once daily exhibit a mean plasma monomethyl fumarate AUC_(0→∞)ranging from about 2.6 h·mg/L to about 5.5 h·mg/L, including allintegers and fractions within the specified ranges. In another aspect,the composition is provided in a dosage form containing a total amountof about 340 mg to about 440 mg of a fumarate ester, wherein subjectsadministered the dose form once daily exhibit a mean plasma monomethylfumarate AUC_(0→∞) ranging from about 5.6 h·mg/L to about 7.5 h·mg/L,including all integers and fractions within the specified ranges. Inanother aspect, the composition is provided in a dosage form containinga total amount of about 340 mg to about 440 mg of a fumarate ester,wherein subjects administered the dose form once daily exhibit a meanplasma monomethyl fumarate AUC_(0→∞) ranging from about 7.6 h·mg/L toabout 11.5 h·mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 340 mg to about 440 mg ofa fumarate ester, wherein subjects administered the dose form once dailyexhibit a mean plasma monomethyl fumarate AUC_(0→∞) ranging from about10.5 h·mg/L to about 15.5 h·mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 340 mg toabout 440 mg of a fumarate ester, wherein subjects administered the doseform once daily exhibit a mean plasma monomethyl fumarate AUC_(0→∞) ofat least about 1.0 h·mg/L, at least 1.2 h·mg/L, at least 1.4 h·mg/L, atleast 1.6 h·mg/L, at least 1.8 h·mg/L, at least 2.0 h·mg/L, at least 2.3h·mg/L, at least 2.6 h·mg/L, at least 2.9 h·mg/L, at least 3.2 h·mg/L,at least 3.5 h·mg/L, at least 3.8 h·mg/L, at least 4.1 h·mg/L, at least4.4 h·mg/L, at least 4.7 h·mg/L, at least 5 h·mg/L, at least 5.3 h·mg/L,at least 5.6 h·mg/L, at least 5.9 h·mg/L, at least 6.2 h·mg/L, at least6.5 h·mg/L, at least 6.8 h·mg/L, at least 7.1 h·mg/L, at least 7.4h·mg/L, at least 7.7 h·mg/L, at least 8.0 h·mg/L, at least 8.3 h·mg/L,at least 8.6 h·mg/L, at least 8.9 h·mg/L, at least 9.2 h·mg/L, at least9.5 h·mg/L, at least 9.8 h·mg/L, at least 10.1 h·mg/L, at least 10.4h·mg/L, at least 10.7 h·mg/L, at least 11.0 h·mg/L, at least 11.3h·mg/L, at least 11.6 h·mg/L, at least 11.9 h·mg/L, at least 12.2h·mg/L, at least 12.5 h·mg/L, at least 12.8 h·mg/L, at least 13.1h·mg/L, at least 13.4 h·mg/L, at least 13.7 h·mg/L, at least 14 h·mg/L,at least 14.3 h·mg/L, at least 14.6 h·mg/L, at least 14.9 h·mg/L, atleast 15.2 h·mg/L, or at least 15.5 h·mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 340 mg to about 440 mg of a fumarateester, wherein subjects administered the dose form once daily exhibit amean plasma monomethyl fumarate T_(max) ranging from about 1.5 hours toabout 10.5 hours including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 340 mg to about 440 mg ofa fumarate ester, wherein subjects administered the dose form once dailyexhibit a mean plasma monomethyl fumarate T_(max) ranging from about 1.6hours to about 2.5 hours, including all integers and fractions withinthe specified ranges. In another aspect, the composition is provided ina dosage form containing a total amount of about 340 mg to about 440 mgof a fumarate ester, wherein subjects administered the dose form oncedaily exhibit a mean plasma monomethyl fumarate T_(max) ranging fromabout 2.6 hours to about 5 hours, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 340 mg toabout 440 mg of a fumarate ester, wherein subjects administered the doseform once daily exhibit a mean plasma monomethyl fumarate T_(max)ranging from about 5.1 hours to about 7.5 hours, including all integersand fractions within the specified ranges. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 340 mg to about 440 mg of a fumarate ester, wherein subjectsadministered the dose form once daily exhibit a mean plasma monomethylfumarate T_(max) ranging from about 7.6 hours to about 8.5 hours,including all integers and fractions within the specified ranges. Inanother aspect, the composition is provided in a dosage form containinga total amount of about 340 mg to about 440 mg of a fumarate ester,wherein subjects administered the dose form once daily exhibit a meanplasma monomethyl fumarate T_(max) ranging from about 8.6 hours to about10.6 hours, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 340 mg to about 440 mg of a fumarateester, wherein subjects administered the dose form once daily exhibit amean plasma monomethyl fumarate T_(max) of at least 1.6 hours, at least1.8 hours, at least 2 hours, at least 2.2 hours, at least 2.4 hours, atleast 2.6 hours, at least 2.8 hours, at least 3 hours, at least 3.2hours, at least 3.4 hours, at least 3.6 hours, at least 3.8 hours, atleast 4 hours, at least 4.2 hours, at least 4.4 hours, at least 4.6hours, at least 4.8 hours, at least 5 hours, at least 5.2 hours, atleast 5.4 hours, at least 5.6 hours, at least 5.8 hours, at least 6hours, at least 6.2 hours, at least 6.4 hours, at least 6.6 hours, atleast 6.8 hours, at least 7 hours, at least 7.2 hours, at least 7.4hours, at least 7.6 hours, at least 7.8 hours, at least 8 hours, atleast 8.2 hours, at least 8.4 hours, at least 8.6 hours, at least 8.8hours, at least 9.0 hours, at least 9.2 hours, at least 9.4 hours, atleast 9.6 hours, at least 9.8 hours, at least 10 hours, at least 10.2hours, at least 10.4 hours, or at least 10.6 hours.

Another embodiment described herein is a pharmaceutical composition fortreating, prophylaxis, or amelioration of general autoimmune orneurodegenerative disorders, comprising a fumarate ester, wherein thecomposition exhibits an in vitro dissolution rate (% dissolution perminute) at pH 6.8, as described herein in any one of Drawings 2-14, 16,or 20-23.

Another embodiment described herein is a pharmaceutical composition fortreating, prophylaxis, or amelioration of general autoimmune orneurodegenerative disorders, including but not limited to multiplesclerosis or psoriasis, comprising a fumarate ester, wherein thecomposition exhibits an in vitro dissolution rate comprising about 10%to about 80% dissolution after about 5 minutes to about 480 minutes atpH 6.8, including all integers and fractions within the specified rangesof dissolution and time. In another aspect, the in vitro dissolutionrate at pH 6.8 is about 50% after about 20 minutes to about 1080minutes, including all integers and fractions within the specifiedranges of dissolution and time. In one aspect, the in vitro dissolutionrate at pH 6.8 is about 50% after about 5 min, is about 50% after about10 min, about 50% after about 20 min, about 50% after about 30 min,about 50% after about 40 min, about 50% after about 50 min, about 50%after about 60 min, about 50% after about 70 min, about 50% after about80 min, about 50% after about 90 min, about 50% after about 120 min,about 50% after about 150 min, about 50% after about 180 min, about 50%after about 210 min, about 50% after about 240 min, about 50% afterabout 300 min, is about 50% after about 330 min, about 50% after about360 min, is about 50% after about 390 min, about 50% after about 420min, about 50% after about 480 min, about 50% after about 540 min, about50% after about 600 min, about 50% after about 660 min, about 50% afterabout 720 min, about 50% after about 780 min, about 50% after about 840min, about 50% after about 900 min, about 50% after about 960 min, orabout 50% after 1080 min. In another aspect, the in vitro dissolutionrate at pH 6.8 is about 50% after about 0.5 hour, about 50% after about1 hour, about 50% after about 2 hours, about 50% after about 3 hours,about 50% after about 4 hours, about 50% after about 5 hours, about 50%after about 6 hours, about 50% after about 7 hours, about 50% afterabout 8 hours, about 50% after about 9 hours, about 50% after about 10hours, about 50% after about 11 hours, about 50% after about 12 hours,about 50% after about 13 hours, about 50% after about 14 hours, about50% after about 15 hours, about 50% after about 16 hours, about 50%after about 17 hours, or about 50% after about 18 hours. In one aspect,the in vitro dissolution rate at pH 6.8 is about 50% after about 10minutes. In another aspect, the in vitro dissolution rate at pH 6.8 isabout 50% after about 20 minutes. In another aspect, the in vitrodissolution rate at pH 6.8 is about 50% after about 45 minutes. Inanother aspect, the in vitro dissolution rate at pH 6.8 is about 50%after about 60 minutes. In one aspect, the in vitro dissolution rate atpH 6.8 is about 50% after about 120 minutes. In another aspect, the invitro dissolution rate at pH 6.8 is about 50% after about 180 minutes.In another aspect, the in vitro dissolution rate at pH 6.8 is about 50%after about 240 minutes. In one aspect, the in vitro dissolution rate atpH 6.8 is about 50% after about 480 minutes.

Another embodiment described herein is a method for manufacturing anoral pharmaceutical composition comprising the steps of:

-   -   (a) introducing mono- and di-glycerides into a 200 L mixing        vessel, adding polyvinylpyrrolidone, and mixing at 400±200 rpm        at 60±5° C. for not less than 30 min until the solution is        clear;    -   (b) adding polyoxyl 40 hydrogenated castor oil and mixing the        solution at 400±200 rpm at 60±5° C. for not less than 30 min        until the solution is clear;    -   (c) adding lactic acid and mixing at 400±200 rpm at 60±5° C. for        not less than 30 min until uniformly blended;    -   (d) cooling the solution in 200 L tank to 25±5° C. while mixing        at 400±200 rpm (a placebo fill can be removed at this step);    -   (e) vacuum transferring the solution to a 500 L vacuum deaerator        at 20±5° C. and mixing under vacuum for no less than 5 min;    -   (f) introducing solid particles of the fumarate ester API (PSD:        40-150 μm) into the deaerator vessel and homogenizing the        suspension for no less than 15 min;    -   (g) vacuum transferring the suspension to a 200 L medicine tank        and deaerating no less than 30 min at 20±5° C.; and    -   (h) homogenizing to form a final suspension at 10-50 rpm.

When the pharmaceutical composition is encapsulated in a soft capsule,the following steps are included:

-   -   (i) preparing a gel mass composition comprising a film-forming,        water-soluble polymer, an appropriate plasticizer, and solvent;    -   (j) casting the gel mass into films or ribbons using        heat-controlled drums or surfaces;    -   (k) transferring the homogenized suspension (h) to an        encapsulation line;    -   (l) encapsulating the homogenized fill solution within the gell        mass films or ribbons using rotary dye encapsulation;    -   (m) drying and finishing capsules;    -   (n) optionally, pre-coating capsules with a sub-coating and        drying;    -   (o) optionally, coating capsules with a coating and drying;    -   (p) optionally, coating capsules with a top coating and drying;        and    -   (q) post processing and packaging.

An analagous process can be used to produce pharmaceutical compositionscomprising soybean oil where steps (a)-(c) above are replaced with (r)and (s):

-   -   (r) introducing soybean oil into a 200 L mixing vessel and        mixing at 400±200 rpm at 60±5° C. for not less than 30 min until        the solution is clear;    -   (s) optionally, adding lactic acid and mixing at 400±200 rpm at        60±5° C. for not less than 30 min until uniformly blended;    -   and then resuming with step (d). If lactic acid is omitted from        the formulation, then step (s) is omitted and the process has        step (r) followed by step (d).

When pharmaceutical composition is encapsulated in a hard capsule, thefollowing steps are included instead of (i)-(q) for soft capsules:

-   -   (i) preparing a gel mass composition comprising a film-forming,        water-soluble polymer, an appropriate plasticizer, and solvent;    -   (j) using the gel mass to form hard capsules via dip-molding and        spinning, drying, stripping, and trimming the capsules,    -   (k) transferring the homogenized suspension (h) to an        encapsulation line;    -   (l) filling the capsules with the homogenized suspension;    -   (m) capping and finishing the capsules;    -   (n) optionally, pre-coating capsules with a sub-coating and        drying;    -   (o) optionally, coating capsules with a coating and drying;    -   (p) optionally, coating capsules with a top coating and drying;        and    -   (q) post processing and packaging.

Another embodiment described herein is a method for treating aneurological disease, neurodegenerative disease, autoimmune disease, oran iatrogenic disease or disorder comprising orally administering one ormore doses of one or more fumarate esters described herein to a patientin need thereof, wherein the administration activates or modulates oneor more cellular signaling pathways. In one aspect, the cellularsignaling pathway comprises the nuclear erythroid-derived 2-like 2(Nrf2) dependent antioxidant response element (ARE) pathway. Withoutbeing bound by any theory, it is believed that at least one aspect ofthe pharmacological activity of the fumarate esters described hereinexert an anti-inflammatory and neuroprotective effect in patients with,for example, multiple sclerosis or psoriasis, by activating the Nrf2cellular signaling pathway. Although not completely understood, the Nrf2pathway is involved in the cellular response to oxidative stress, whichhas been linked to neuronal degeneration in multiple sclerosis and inother neurodegenerative or autoimmune diseases (e.g., HIV), see, e.g.,Gao et al., Clin. Pharmacol. 6:19-34 (2014), which is incorporated byreference herein for its teachings thereof.

It is currently thought that under basal conditions, Nrf2 is sequesteredin the cytoplasm to the actin-bound Kelch-like ECH-associated protein 1(Keap1). Keap1 associates with the Cullin3 ubiquitin ligase adaptorprotein, which positions Keap1 and its substrate in proximity (e.g.,NRF2) to the E3 ubiquitin ligase Rbx1. Thus, under normal conditions,the substrate (Nrf2) is polyubiquitinated and targeted for degradation.In response to oxidative stress, Nrf2 is released from the Keap1/Nrf2complex, preventing its degradation resulting in the concommitanttranslocation of NRF2 to the nucleus and activation of ARE-mediated genetranscription. Based on this understanding, any of the non-limitingmethods for determining the activation of Nrf2 may be used that arefurther described herein. See U.S. Pat. No. 8,399,514, which isincorporated by reference herein for its teachings thereof.

Nrf2 activation may be determined by assessing the in vitro activationlevels of Nrf2 and/or Nrf2 mRNA or protein expression levels. Thesequence of the promoter region of the Nrf2 gene (−1065 to −35) isknown. In vitro Nrf2 activation may be measured using a cell modelsystem transfected or transduced with an expression construct containingthe Nrf2 promoter element described above and an artificial reportergene (e.g., luciferase or a fluorescent reporter gene (GFP, RFP, YFPetc.). See, e.g., Chan et al., Proc. Natl. Aacd. Sci. USA 93:13943-13948(1996) and Kwak et al., Mol. Cell. Biol. 22(9):2883-2892 (2002), each ofwhich is incorporated by reference herein for their teachings thereof.Nrf2 activation may be assessed by measuring reporter gene expression intreated vs. non-treated cells using standard imaging or fluorescencequantification techniques. Alternatively, PCR (e.g., qRT-PCR) orNorthern blotting may be used to determine expression levels of Nrf2mRNA, or Western blotting to determine Nrf2 protein levels. See, e.g.,Kwak et al., Mol. Cell. Biol. 22(9):2883-2892 (2002) and Kwak et al.,Mol. Med. 7:135-145 (2001), each of which is incorporated by referenceherein for their teachings thereof. Antibodies against Nrf2 are can beproduced by methods known in the art and are commercially availablefrom, for example, Stressgen®, Enzo Life Sciences.

In addition, Nrf2 activation may be assessed by determining thesubcellular localization and/or nuclear translocation of Nrf2 in treatedvs. non-treated cells. Such assays include cell staining, or analysis ofcytoplasmic versus nuclear cell extracts. For example, an Nrf2-greenfluorescence protein (GFP) fusion protein construct can be introducedinto cells and visualized as described in, e.g., Kraft et al., J.Neurosci. 24:1101-1112 (2004) and in Satoh et al., Proc. Natl. Aacd.Sci. USA 103(3):768-773 (2006).

Nrf2 activation may be determined through indirect measurement of theexpression levels and/or activity of one or more genes under the controlof Nrf2 in treated vs. non-treated cells. For example, the expressionlevels of NADPH dehydrogenase quinone 1 (NQO1) may be determined using,for example, qRT-PCR, Northern blotting, or Western blotting, see, e.g.,Wierinckx et al., J. Neuroimmunology 166:132-143 (2005). Methods formeasuring enzymatic activity of NQO1, using menadione as a substrate,are described in Dinkova-Kostova et al., Proc. Natl. Aacd. Sci. USA98:3404-09 (2001).

The cell type being contacted with the one or more fumarate estersdescribed herein may comprise a neuron or a neuronal cell line, a coloncarcinoma cell line (e.g., DLD1), a neuroblastoma cell line (e.g., SkNSHor IMR32), or a primary immune cell (e.g., a monocyte or T-lymphocyte orB-lymphocyte). The cell may be a cell in culture (in vitro) or be insideof a mammal (in vivo). Alternatively, endogenous Nrf2 activation may bedetermined by measuring the levels of Nrf2 or a Nrf2 regulated gene(e.g., NQO1) in a primary cell or cell population (e.g., a monocyte,T-lymphocyte, or neuronal cell) taken from a human patient havingneurological disease, neurodegenerative disease, or autoimmune disease(e.g., multiple sclerosis or psoriasis).

It will be apparent to one of ordinary skill in the relevant art thatsuitable modifications and adaptations to the compositions,formulations, methods, processes, and applications described herein canbe made without departing from the scope of any embodiments or aspectsthereof. The compositions and methods provided are exemplary and are notintended to limit the scope of any of the specified embodiments. All ofthe various embodiments, aspects, and options disclosed herein can becombined in any and all variations or iterations. The scope of thecompositions, formulations, methods, and processes described hereininclude all actual or potential combinations of embodiments, aspects,options, examples, and preferences herein described. The exemplarycompositions and formulations described herein may omit any component,substitute any component disclosed herein, or include any componentdisclosed elsewhere herein. The ratios of the mass of any component ofany of the compositions or formulations disclosed herein to the mass ofany other component in the formulation or to the total mass of the othercomponents in the formulation are hereby disclosed as if they wereexpressly disclosed. Should the meaning of any terms in any of thepatents or publications incorporated by reference conflict with themeaning of the terms used in this disclosure, the meanings of the termsor phrases in this disclosure are controlling. Furthermore, theforegoing discussion discloses and describes merely exemplaryembodiments. All patents and publications cited herein are incorporatedby reference herein for the specific teachings thereof.

EXAMPLES Example 1 DMF Enteric Soft Capsule Fills

Based on results of dimethyl fumarate (DMF) solubility testing invarious lipid or lipophilic vehicles (data not shown), two formulationswere selected for further studies and encapsulated in enteric softgelatin capsules: one having polyethylene glycol and one with mediumchain mono- and diglycerides. Organic acids such as caprylic acid,lactic acid, or oleic acid, were incorporated into the matrix fill toprevent the hydrolysis of dimethyl fumarate and to retain entericproperties of the shell. Application batches of enteric soft capsuleswere prepared by rotary die encapsulation using the fill compositionsshown in Table 10.

TABLE 10 DMF Fill Compositions Capmul ® MCM PEG Matrix Matrix (A413-A)(A413-B) Ingredient mg/capsule % wt mg/capsule % wt Dimethyl Fumarate240 32.0 240 32.0 (Mean PSD: 80 μm) Capmul ® MCM 367.5 49.0 PEG 400 — —382.5 51.0 Povidone K30 52.5 7.0 37.5 5.0 Tween ® 80 75 10.0 75 10.0Lactic acid 15 2.0 15 2.0 TOTAL 750 100% 750 100%

The enteric soft capsules comprising the matrix formulations shown inTable 9 were subject to two-stage dissolution experiments in a USPApparatus II (e.g., paddle method at 100 rpm). For these experiments,the capsules were introduced in to simulated gastric fluid, 0.1 N HCl,pH 1.2, for 2 hours. After 2 hours, the capsules were transferred tosimulated intestinal fluid, phosphate buffer, pH 6.8. The results areshown in FIG. 2. The results show that the capsules retain their entericproperties for at least 2 hours in simulated gastric fluid at pH 1.2.Both types of capsules released DMF shortly (˜10 minutes) after beingtransferred to simulated intestinal fluid, pH 6.8. The enteric softcapsules comprising matrices comprising PEG 400 released DMF morerapidly than those comprising Capmul® MCM (ABITEC Corp.; medium chainmono- and di-glycerides).

Example 2

Stability of the Enteric Soft Capsules over Time

The temporal stability of the dimethyl fumarate enteric soft capsulefill formulation shown in Table 11 was assessed. A sample of DMF entericsoft capsules was subjected to accelerated aging by a 1 month ofexposure to 40° C. and 75% relative humidity conditions and thenevaluated in two-stage dissolution experiment. A second sample of DMFenteric soft capsules was subject to two-stage dissolution shortly aftermanufacturing. Both sets of enteric capsules remained intact in theacidic conditions for at least 2 hours. FIG. 3. The freshly manufacturedcapsules released DMF slightly faster than the age-accelerated capsuleswhen the pH was shifted to 6.8 (phosphate buffer).

TABLE 11 DMF Fill Composition Ingredient mg/capsule % weight Dimethylfumarate 240 32.0 (Mean PSD: 80 μm) Capmul ® MCM 367.5 49.0 Povidone K30 52.5 7.0 Tween ® 80 75 10.0 Lactic acid 15 2.0 TOTAL 750 mg 100%

Example 3 DMF Release in Enteric Soft Capsules

A developmental batch of enteric soft capsules comprising a Capmul® MCMmatrix containing particles of dimethyl fumarate (Table 11) was subjectto two-stage dissolution at pH 1.2 in simulated gastric fluid for 2hours, then the buffer was changed to phosphate buffer, pH 6.8,containing 2% Cremophor® RH 40. FIG. 4. The enteric capsules remainedintact in the acidic condition, and then began releasing DMF within 20minutes of the pH-shift to simulated intestinal fluid.

Example 4 Surfactants Affect DMF Release Rate

Enteric soft capsules were prepared with matrices comprising 10% Tween®80 (Uniqema, ICI Americas Inc; polyoxyethylene (80) sorbitan monooleate;e.g., polysorbate 80) or 10% Cremophor® RH 40 (BASF SE; polyoxyl 40hydrogenated castor oil) (Table 12) and then tested in dissolutionexperiments at pH 6.8. FIG. 5. The enteric soft capsules with fillscontaining Cremophor® released DMF much more rapidly than thosecontaining Tween® 80.

TABLE 12 DMF Fill Compositions Tween ® Cremophor ® 80 Matrix RH 40Matrix Ingredient mg/capsule % wt mg/capsule % wt Dimethyl Fumarate 24032.0 240 32.0 (Mean PSD: 80 μm) Capmul ® MCM 367.5 49.0 367.5 49.0Povidone K 30 52.5 7.0 52.5 7.0 Tween ® 80 75 10.0 — — Cremophor ® RH 40— — 75 10.0 Lactic acid 15 2.0 15 2.0 TOTAL 750 100% 750 100%

Example 5 Polyvinylpyrrolidone Concentration Affects DMF Release Rate

Enteric soft capsules prepared containing fills with of 3% or 5%concentrations of Povidone K30 (e.g., PVP; 30,000 average MW) (Table 13)were tested in dissolution experiments at pH 6.8. FIG. 6. The entericsoft capsules with matrices containing 5% Povidone K30 released DMF morerapidly at pH 6.8 than those with fills containing 3% Povidone K30.

TABLE 13 DMF Fill Compositions 3% PVP 5% PVP Ingredient mg/capsule % wtmg/capsule % wt Dimethyl Fumarate 240 32.0 240 32.0 (Mean PSD: 80 μm)Capmul ® MCM 397.5 53 382.5 51 Cremophor ® RH 40 75 10.0 75 10.0Povidone K 30 22.5 3.0 37.5 5.0 Lactic acid 15 2.0 15 2.0 TOTAL 750 100%750 100% Viscosity: 43191 Cp 122000 Cp

Based on the foregoing formulation studies, the Capmul® MCM-basedformulation was selected for further analysis. A batch was manufacturedusing the formulation below (Table 14).

TABLE 14 DMF Fill Composition Ingredient mg/capsule % weight DimethylFumarate 240 32 (Mean PSD: 80 μm) Capmul ® MCM 375 50 Cremophor ® RH 4075 10 Povidone K 30 52.5 7 Lactic acid 15 2 TOTAL 750 mg 100%

Example 6 DMF Enteric Soft Capsules Are Amenable to Controlled orExtended Release

The release profile of DMF is modified by varying the enteric softcapsule shell composition or by altering the fill composition orparticle size of the active ingredient. Three different release profileswere observed under two-stage dissolution experiments. All enteric softcapsules were resistant to acid for at least 2 hours, and beginreleasing DMF upon transition to pH 6.8. FIG. 7. A release profile wasobserved in an enteric soft capsule comprising a matrix of Capmul® MCMand Cremophor® RH 40 (Table 15; Release Profile 1). A different releaseprofile was observed with an enteric soft capsule shell comprising aCapmul® MCM and Tween® 80 matrix (Table 11; Release Profile 2). Anotherrelease profile was observed with an enteric soft capsule shellcomprising a matrix of soybean oil, Tween® 80, and solid particles ofDMF having a mean particle distribution size of 148 μm (Table 16;Release Profile 3).

TABLE 15 DMF Fill Composition (P31) Ingredient mg/capsule % weightDimethyl fumarate 240 32.0 (Mean PSD: 80 μm) Capmul ® MCM 367.5 49.0Cremophor ® RH 40 75 10.0 Povidone K 30 52.5 7.0 Lactic acid 15 2.0TOTAL 750 mg 100%

TABLE 16 DMF Fill Composition (P6) Ingredient mg/capsule % weightDimethyl fumarate 240 43.6 (Mean PSD 148 μm) Soybean oil 285.25 51.9Aerosil 200 75 10.0 Tween ® 80 11 2.0 Caprylic acid 11 2.0 TOTAL 550 mg100%

Example 7 DMF Particle Size Affects Release Rate

Enteric soft capsules comprising matrices with DMF particles ofdiffering mean particle size distributions as shown in Table 17 weresubject to dissolution at pH 6.8. FIG. 8.

TABLE 17 Matrices with Varying DMF Particle Sizes Formulation A (P7) B(P8) C (P9) Ingredient mg/capsule % weight mg/capsule % weightmg/capsule % weight DMF Mean PSD: 240 43.6 — — — — 168 μm DMF Mean PSD:— — 240 43.6 — — 148 μm DMF Mean PSD: — — — — 240 43.6 90 μm PEG 400 24444.4 244 44.4 244 44.4 Povidone K30 — — — — — — Tween ® 80 55 10 55 1055 10 Caprylic acid 11 2 11 2 11 2 Lactic acid — — — — — — TOTAL 550 100550 100 550 100 Formulation D (P25) E (P15) F (P23) Ingredientmg/capsule % weight mg/capsule % weight mg/capsule % weight DMF MeanPSD: 240 34.3 — — — — 76 μm DMF Mean PSD: — — 240 28.2 240 28.2 26 μmPEG 400 355 50.7 508 59.8 482 56.8 Povidone K30 21 3 — — 26 3 Tween ® 8070 10 85 10 85 10 Caprylic acid — — 17 2 17 2 Lactic acid 14 2 — — — —TOTAL 700 100 850 100 850 100

Example 8

Enteric soft capsules comprising various matrices comprising DMFparticles having particle size distribution of d90≤90 μm were preparedand analyzed in two stage (pH 1.2 and pH 6.8) or single stage (pH 6.8)dissolution experiments (data not shown). (Tables 18-20).

TABLE 18 Various DMF Fill Compositions Formulation A (P32) B (P33) C(P34) Ingredient mg/capsule % weight mg/capsule % weight mg/capsule %weight DMF 240 32.0 240 32.0 240 32.0 PSD: d90 ≤ 90 μm Capmul ® MCM 36048.0 322.5 43.0 352.5 47.0 Cremophor ® RH 40 112.5 15.0 150 20.0 112.515.0 Lactic acid 37.5 5.0 37.5 5.0 37.5 5.0 TOTAL 750 100 750 100 750100 D (P35) E (P37) F (P38) Ingredient mg/capsule % weight mg/capsule %weight mg/capsule % weight DMF 240 32.0 240 32.0 240 32.0 PSD: d90 ≤ 90μm Capmul ® MCM 315 42.0 360 48.0 360 48.0 Cremophor ® RH 40 150 20.0 7510.0 75 10.0 Lactic acid 37.5 5.0 37.5 5.0 37.5 5.0 Povidone K 30 7.51.0 — — — — PEG 400 — — 37.5 5.0 — — Polypropylene glycol — — — — 37.55.0 TOTAL 750 100 750 100 750 100 G (P39) H (P41) I (P43) Ingredientmg/capsule % weight mg/capsule % weight mg/capsule % weight DMF 240 28.2240 28.2 240 28.2 PSD: d90 ≤ 90 μm Capmul ® MCM 482.5 56.8 397.5 46.8397.5 46.8 Cremophor ® RH 40 85 10.0 85 10.0 — — Lactic acid 42.5 5.042.5 5.0 42.5 5.0 Labrasol ® — — 85 10.0 170 20.0 TOTAL 850 100 850 100850 100

TABLE 19 Various DMF Fill Compositions Formulation A (P44) B (P45) C(P46) Ingredient mg/capsule % weight mg/capsule % weight mg/capsule %weight DMF 240 28.2 240 28.2 240 28.2 PSD: d90 ≤ 90 μm Capmul ® MCM 37243.8 355 41.8 329.5 38.8 Cremophor ® RH 40 85 10.0 85 10.0 85 10.0Lactic acid 42.5 5.0 42.5 5.0 42.5 5.0 Labrasol ® 85 10.0 85 10.0 8510.0 Povidone K 30 25.5 3.0 — — 25.5 3.0 Mannitol — — 42.5 5.0 42.5 5.0TOTAL 850 100 850 100 850 100 D (P47) E (P48) F (P49) Ingredientmg/capsule % weight mg/capsule % weight mg/capsule % weight DMF 240 28.2240 28.2 240 28.2 PSD: d90 ≤ 90 μm Capmul ® MCM 384.75 45.3 284.19533.43 312.5 36.76 Cremophor ® RH 40 85 10.0 85 10.0 85 10.0 Lactic acid42.5 5.0 42.5 5.0 42.5 5.0 Povidone K 30 12.75 1.5 — — — — Labrasol ® —— 85 10.0 85 10.0 PEG 3350 85 10.0 113.305 13.33 85 10.00 TOTAL 850 100850 100 850 100 G (P50) H (P51) I (P52) Ingredient mg/capsule % weightmg/capsule % weight mg/capsule % weight DMF 240 28.2 240 28.2 240 28.2PSD: d90 ≤ 90 μm Capmul ® MCM 333.75 39.26 287 33.76 333.75 39.26Cremophor ® RH 40 85 10.0 85 10.00 85 10.00 Lactic acid 42.5 5.0 42.55.0 42.5 5.0 Labrasol ® 85 10.0 85 10.0 85 10.00 PEG 3350 63.75 7.50 — —— — Povidone K 17 — — 25.5 3.00 — — Mannitol — — 85 10.00 — —Crospovidone-CL — — — — 63.75 7.50 TOTAL 850 100 850 100 850 100

TABLE 20 Various DMF Fill Compositions Formulation A (P53) B (P54) C(P55) Ingredient mg/capsule % weight mg/capsule % weight mg/capsule %weight DMF 240 28.24 240 28.24 240 28.24 PSD: d90 ≤ 90 μm Capmul ® MCM397.5 46.76 397.5 46.76 390.7 45.96 Cremophor ® RH 40 85 10.00 85 10.0085 10.00 Lactic acid 42.5 5.00 42.5 5.00 42.5 5.00 PEG 3350 85 10.00 — —— — PEG 400 — — — — 42.5 5.00 Lutrol ® F 68 — — 85 10.00 — — Sodiumlauryl sulfate — — — — 49.3 5.80 TOTAL 850 100 850 100 850 100 D (P56) E(P57) F (P58) Ingredient mg/capsule % weight mg/capsule % weightmg/capsule % weight DMF 240 28.24 240 28.24 240 28.24 PSD: d90 ≤ 90 μmCapmul ® MCM 355 41.76 363.5 42.76 355 41.76 Cremophor ® RH 40 85 10.0085 10.00 85 10.00 Lactic acid 42.5 5.00 42.5 5.00 42.5 5.00 PEG 400 8510.00 85 10.00 85 10.00 Crospovidone CL 42.5 5.00 — — — — CrospovidoneCL-F — — 34 4.00 — — Crospovidone CL-M — — — — 42.5 5.00 TOTAL 850 100850 100 850 100 G (P59) H (P60) I (P61) Ingredient mg/capsule % weightmg/capsule % weight mg/capsule % weight DMF 240 28.24 240 28.24 24028.24 PSD: d90 ≤ 90 μm Capmul ® MCM 312.5 36.76 355 41.76 329.5 38.76Cremophor ® RH 40 85 10.00 85 10.00 85 10.00 Lactic acid 42.5 5.00 42.55.00 42.5 5.00 Labrasol ® 85 10.00 85 10.00 85 10.00 Pearlitol ® Flash85 10.00 — — 42.5 5.00 Croscarmellose — — 42.5 5.00 25.5 3.00 SodiumTOTAL 850 100 850 100 850 100

Example 9 Capsule Shell Thickness Affects Release Rate

Application batches of enteric soft capsules with shell thicknesses of0.028 inches or 0.033 inches were prepared comprising DMF particleshaving particle size distributions of d90≤90 μm in various matrices(Table 2′) and analyzed in two stage (pH 1.2 and pH 6.8) dissolutionexperiments (FIG. 9).

TABLE 21 DMF Fill Compositions A (APP021214) B (APP020714) (0.028 inchribbon) (0.033 inch ribbon) Ingredient mg/capsule % wt mg/capsule % wtDimethyl Fumarate 240 28.2 240 28.2 PSD: d90 ≤ 90 μm Capmul ® MCM 44051.8 465.5 54.8 Cremophor ® 85 10.0 85 10.0 RH 40 Povidone K30 42.5 5.042.5 5.0 PEG 400 — — 42.5 5.0 Crospovidone-CL 17 2.0 — — TOTAL 850 100%850 100% C (APP022414-A) D (APP022414-B) (0.028 inch ribbon) (0.028 inchribbon) Ingredient mg/capsule % wt mg/capsule % wt Dimethyl Fumarate 24028.24 240 28.24 PSD: d90 ≤ 90 μm Capmul ® MCM 312.5 36.76 312.5 36.76Cremophor ® 85 10.0 85 10.0 RH 40 Povidone K30 42.5 5.0 42.5 5.0 PEG 600127.5 15.0 — — Crospovidone-CL 42.5 5.0 — — Labrasol ® — — 85 10.0Pearlito ® Flash — — 85 10.0 TOTAL 850 100% 850 100%

Example 10

A GMP batch of enteric soft capsules (0.038-inch shell thickness)comprising DMF particles having a particle size distribution of PSD:d90≤90 μm was prepared with the matrix composition shown in Table 22 andanalyzed in two stage (pH 1.2 and pH 6.8) dissolution experiments (FIG.14) and compared to application batches (Table 19).

TABLE 22 GMP DMF Fill Composition Ingredient mg/capsule % weightDimethyl fumarate 240 32.0 PSD: d90 ≤ 90 μm Capmul ® MCM 375 50.0Cremophor ® RH 40 75 10.0 Povidone K 30 22.5 3.0 Lactic acid 37.5 5.0TOTAL 750 mg 100%

Example 11 Povidone K30 and PEG 600 Affect DMF Release Rate

DMF matrices were prepared with and without Povidone K30 or PEG 600(Table 23) and analyzed in single stage (pH 6.8) dissolution experiments(FIG. 11).

TABLE 23 DMF Fill Compositions A (P62) B (P63) Ingredient mg/capsule %weight mg/capsule % weight Dimethyl fumarate 240 28.2 240 28.24 PSD: d90≤ 90 μm Capmul ® MCM 482.5 56.8 384.75 45.26 Cremophor ® 85 10.0 8510.00 RH 40 Povidone K 30 — — 12.75 1.50 PEG 600 — — 85 10.00 Lacticacid 42.5 5.0 42.5 5.0 TOTAL 850 mg 100% 850 mg 100% C (P64) D (P65)Ingredient mg/capsule % weight mg/capsule % weight Dimethyl fumarate 24028.24 240 28.24 PSD: d90 ≤ 90 μm Capmul ® MCM 457 53.76 372 43.76Cremophor ® 85 10.00 85 10.00 RH 40 Povidone K 30 25.5 3.00 25.5 3.00PEG 600 — — 85 10.00 Lactic acid 42.5 5.00 42.5 5.00 TOTAL 850 mg 100%850 mg 100%

Example 12

A batch of enteric soft capsules (0.038-inch shell thickness) comprisingDMF particles having particle size distribution of PSD: d90≤90 μm wasprepared with the matrix composition shown in Table 24 and analyzed intwo stage (pH 1.2 and pH 6.8) dissolution experiments (FIG. 12). Thisexample provides a lower dose of DMF (120 mg) compared with that shownin Table 11 (240 mg).

TABLE 24 DMF Fill Composition Ingredient mg/capsule % weight Dimethylfumarate 120 28.2 PSD: d90 ≤ 90 μm Capmul ® MCM 228.5 53.8 Cremophor ®RH 40 42.5 10.0 Povidone K 30 12.75 3.0 Lactic acid 21.25 5.0 TOTAL 425mg 100%

Example 13

A batch of enteric soft capsules (0.038-inch shell thickness) comprisingmonomethyl fumarate (MMF) particles having particle size distribution ofPSD: d90≤90 μm was prepared with the matrix composition shown in Table25. This example provides MMF (240 mg).

TABLE 25 MMF Fill Composition Ingredient mg/capsule % weight Monomethylfumarate 240 28.2 PSD: d90 ≤ 90 μm Capmul ® MCM 457 53.8 Cremophor ® RH40 85 10.0 Povidone K 30 25.5 3.0 Lactic acid 42.5 5.0 TOTAL 850 mg 100%

Example 14

A batch of enteric soft capsules (0.038-inch shell thickness) comprisingmonomethyl fumarate (MMF) particles having particle size distribution ofPSD: d90≤90 μm was prepared with the matrix composition shown in Table26. This example provides MMF (480 mg).

TABLE 26 MMF Fill Composition Ingredient mg/capsule % weight Monomethylfumarate 480    48-56.4 PSD: d90 ≤ 90 μm Capmul ® MCM 216-470  25.5-47Cremophor ® RH 40 7.3-120  0.85-12 Povidone K 30 7.3-50  0.85-5  Lacticacid 21.7-50   2.55-5  TOTAL 850 mg-1000 mg 100%

Example 15

Enteric soft capsules comprising particles of dimethyl fumarate,monomethyl fumarate, or a combination thereof having particle sizedistribution of PSD: d90≤90 μm can be prepared with an 850 mg matrix inthe compositions shown in Table 27. This example provides DMF or MMF ina QD formulation (˜480 mg).

TABLE 27 DMF or MMF 850 mg Fill Compositions Percent Weight (%)Ingredient EX1 EX2 EX3 EX4 EX5 EX6 Dimethyl fumarate or 56.4 56.4 56.456.4 56.4 56.4 Monomethyl fumarate PSD: d90 ≤ 90 μm Capmul ® MCM 30.639.95 28.9 28.9 25.5 32.7 Cremophor ® RH 40 8.5 0.85 8.5 8.5 10.2 6.1Povidone K 30 0.85 0.85 2.55 2.55 4.25 1.8 Lactic acid 4.25 2.55 4.254.25 4.25 3.0 TOTAL 100 100 100 100 100 100

Example 16

Enteric soft capsules comprising particles of dimethyl fumarate,monomethyl fumarate, or a combination thereof having particle sizedistribution of PSD: d90≤90 μm can be prepared with a 1000 mg matrix inthe compositions shown in Table 28. This example provides DMF or MMF ina QD formulation (˜480 mg).

TABLE 28 DMF or MMF 1000 mg Fill Compositions Percent Weight (%)Ingredient EX1 EX2 EX3 EX4 EX5 EX6 Dimethyl fumarate or 48 48 48 48 4848 Monomethyl fumarate PSD: d90 ≤ 90 μm Capmul ® MCM 44 36 47 34 34 38.9Cremophor ® RH 40 2 10 1 10 10 7.2 Povidone K 30 1 1 1 3 3 2.2 Lacticacid 5 5 3 5 5 3.6 TOTAL 100 100 100 100 100 100

Example 17 Stability of the Enteric Soft Capsules Over Time

The temporal stability of the dimethyl fumarate enteric soft capsulepharmaceutical composition shown in Table 29 was assessed under threeICH conditions. A sample of DMF enteric soft capsules was subject tochemical analysis and two-stage dissolution shortly after manufacturing(T₀). Samples of DMF enteric soft capsules were subjected to RoomTemperature Conditions (25° C. and 60% relative humidity) for 1 month,2, months, 3 months, and 6 months. Other samples of DMF enteric softcapsules were subjected to Intermediate Conditions (30° C. and 65%relative humidity) for 1 month, 2 months, and 3 months. Additionalsamples of DMF enteric soft capsules were subjected to AcceleratedConditions (40° C. and 75% relative humidity) for 1 month and 2 months.After the designated incubation period, the capsules were chemicallyanalyzed and evaluated in two-stage dissolution experiments at pH 1.2and 6.8 as described herein if conditions permitted (i.e., non-leakingcapsules). Two-stage dissolution results for DMS enteric soft capsulesat T₀, and after 3- and 6-months at Room Temperature Conditions (25° C.and 60% RH) are shown in FIG. 13.

TABLE 29 GMP DMF Fill Composition Ingredient mg/capsule % weightDimethyl fumarate 240 32.0 PSD: d90 ≤ 90 μm Capmul ® MCM 375 50.0Cremophor ® RH 40 75 10.0 Povidone K 30 22.5 3.0 Lactic acid 37.5 5.0TOTAL 750 mg 100%

TABLE 30 GMP DMF Stability Initial 25° C., 60% Relative Humidity T₀ 1 M2 M 3 M 6 M Assay 101.2%   101.0% 102.4% 101.25 98.8% DegradationProducts Monomethyl 0.14% 0.13% 0.14% 0.16% 0.18% Fumarate RRT 0.74 NDND 0.07% 0.09% 0.18% RRT 1.61 0.05% ND ND ND ND RRT 2.18 ND ND ND <0.05%0.09% Total 0.19% 0.13% 0.21% 0.25% 0.45% Degradation Products 30° C.,65% Relative Humidity 40° C., 75% Rel. Humid. 1 M 2 M 3 M 1 M 2 M Assay100.1% 99.4% 99.5% 99.3% 113.1%* Degradation Products Monomethyl 0.14%0.17% 0.22% 0.22% 0.26% Fumarate RRT 0.74 0.14% 0.22% 0.28% 0.3% 0.46%RRT 1.61 0.06% 0.11% 0.14% 0.15% 0.35% RRT 2.18 0.34% 0.5% 0.64% 0.67%1.07% Total 0.14% 0.17% 0.22% 0.22% 0.26% Degradation Products *Datawere collected on fill extracted from leaking capsules. Note: Leakingcapsules were observed at the 2- and 3-month time points for theaccelerated condition (40° C., 75% RH). This was expected for theenteric soft gelatin capsules. The intermediate condition (30° C., 65%RH) and long-term condition (25° C., 60% RH) will be assessed at the12-month and 24-month time points to assess chemical stability.

Example 18

Fill compositions with increasing amounts of one or more fumarate esters(e.g., dimethyl fumarate, monomethyl fumarate, or a combination thereofranging from about 0.5 mmol to about 4.0 mmol) having a particle sizedistribution of PSD: d90≤100 μm in a 750 mg fill are shown in Table 31.Millimole values for DMF or MMF (shaded rows) specify the millimoles ofthe respective species at the specified mass (mg). These fillcompositions may be encapsulated by a soft capsule shell composition asdescribed herein. In one embodiment, the one or more fumarate esterscomprise about 0.5 mmol to about 3.7 mmol FAE. In one embodiment, thefumarate ester (FAE) comprises DMF. In another embodiment, the fumarateester comprises MMF. In another embodiment, the fumarate ester comprisesMMF, DMF, or a combination thereof.

TABLE 31 Fumarate Ester 750 mg Fill Compositions mg/capsule IngredientEX1 EX2 EX3 EX4 EX5 EX6 Fumarate Ester PSD: d90 ≤ 100 μm 80 85 90 95 97100 mmol DMF 0.56 0.59 0.62 0.66 0.67 0.69 mmol MMF 0.61 0.65 0.69 0.730.75 0.77 Capmul ® MCM 535 530 525 520 518 515 Cremophor ® RH 40 75 7575 75 75 75 Povidone K 30 22.5 22.5 22.5 22.5 22.5 22.5 Lactic acid 37.537.5 37.5 37.5 37.5 37.5 TOTAL 750 750 750 750 750 750 Ratio FAE to Fill0.12 0.13 0.14 0.15 0.15 0.15 Percent Weight (%) Fumarate Ester PSD: d90≤ 100 μm 10.7 11.3 12 12.7 12.9 13.3 Capmul ® MCM 71.3 70.7 70 69.3 69.168.7 Cremophor ® RH 40 10 10 10 10 10 10 Povidone K 30 3 3 3 3 3 3Lactic acid 5 5 5 5 5 5 TOTAL 100 100 100 100 100 100 mg/capsuleIngredient EX7 EX8 EX9 EX10 EX11 EX12 Fumarate Ester PSD: d90 ≤ 100 μm105 107 108 110 115 120 mmol DMF 0.73 0.74 0.75 0.76 0.80 0.83 mmol MMF0.81 0.82 0.83 0.85 0.88 0.92 Capmul ® MCM 510 508 507 505 500 495Cremophor ® RH 40 75 75 75 75 75 75 Povidone K 30 22.5 22.5 22.5 22.522.5 22.5 Lactic acid 37.5 37.5 37.5 37.5 37.5 37.5 TOTAL 750 750 750750 750 750 Ratio FAE to Fill 0.16 0.17 0.17 0.17 0.18 0.19 PercentWeight (%) Fumarate Ester PSD: d90 ≤ 100 μm 14 14.3 14.4 14.7 15.3 16Capmul ® MCM 68 67.7 67.6 67.3 66.7 66 Cremophor ® RH 40 10 10 10 10 1010 Povidone K 30 3 3 3 3 3 3 Lactic acid 5 5 5 5 5 5 TOTAL 100 100 100100 100 100 mg/capsule Ingredient EX13 EX14 EX15 EX16 EX17 EX18 FumarateEster PSD: d90 ≤ 100 μm 160 170 180 190 194 200 mmol DMF 1.11 1.18 1.251.32 1.35 1.39 mmol MMF 1.23 1.31 1.38 1.46 1.49 1.54 Capmul ® MCM 455445 435 425 421 415 Cremophor ® RH 40 75 75 75 75 75 75 Povidone K 3022.5 22.5 22.5 22.5 22.5 22.5 Lactic acid 37.5 37.5 37.5 37.5 37.5 37.5TOTAL 750 750 750 750 750 750 Ratio FAE to Fill 0.27 0.29 0.32 0.34 0.350.36 Percent Weight (%) Fumarate Ester PSD: d90 ≤ 100 μm 21.3 22.7 2425.3 25.9 26.7 Capmul ® MCM 60.7 59.3 58 56.7 56.1 55.3 Cremophor ® RH40 10 10 10 10 10 10 Povidone K 30 3 3 3 3 3 3 Lactic acid 5 5 5 5 5 5TOTAL 100 100 100 100 100 100 mg/capsule Ingredient EX19 EX20 EX21 EX22EX23 EX24 Fumarate Ester PSD: d90 ≤ 100 μm 210 214 216 220 230 240 mmolDMF 1.46 1.48 1.50 1.53 1.60 1.67 mmol MMF 1.61 1.64 1.66 1.69 1.77 1.84Capmul ® MCM 405 401 399 395 385 375 Cremophor ® RH 40 75 75 75 75 75 75Povidone K 30 22.5 22.5 22.5 22.5 22.5 22.5 Lactic acid 37.5 37.5 37.537.5 37.5 37.5 TOTAL 750 750 750 750 750 750 Ratio FAE to Fill 0.39 0.400.40 0.42 0.44 0.47 Percent Weight (%) Fumarate Ester PSD: d90 ≤ 100 μm28 28.5 28.8 29.3 30.7 32 Capmul ® MCM 54 53.5 53.2 52.7 51.3 50Cremophor ® RH 40 10 10 10 10 10 10 Povidone K 30 3 3 3 3 3 3 Lacticacid 5 5 5 5 5 5 TOTAL 100 100 100 100 100 100 mg/capsule IngredientEX25 EX26 EX27 EX28 EX29 EX30 Fumarate Ester PSD: d90 ≤ 100 μm 320 340360 380 388 400 mmol DMF 2.22 2.36 2.50 2.64 2.69 2.78 mmol MMF 2.462.61 2.77 2.92 2.98 3.07 Capmul ® MCM 295 275 255 235 227 215Cremophor ® RH 40 75 75 75 75 75 75 Povidone K 30 22.5 22.5 22.5 22.522.5 22.5 Lactic acid 37.5 37.5 37.5 37.5 37.5 37.5 TOTAL 750 750 750750 750 750 Ratio FAE to Fill 0.74 0.83 0.92 1.03 1.07 1.14 PercentWeight (%) Fumarate Ester PSD: d90 ≤ 100 μm 42.7 45.3 48 50.7 51.7 53.3Capmul ® MCM 39.3 36.7 34 31.3 30.3 28.7 Cremophor ® RH 40 10 10 10 1010 10 Povidone K 30 3 3 3 3 3 3 Lactic acid 5 5 5 5 5 5 TOTAL 100 100100 100 100 100 mg/capsule Ingredient EX31 EX32 EX33 EX34 EX35 EX36Fumarate Ester PSD: d90 ≤ 100 μm 420 428 432 440 460 480 mmol DMF 2.912.97 3.00 3.05 3.19 3.33 mmol MMF 3.23 3.29 3.32 3.38 3.54 3.69 Capmul ®MCM 195 187 183 175 155 135 Cremophor ® RH 40 75 75 75 75 75 75 PovidoneK 30 22.5 22.5 22.5 22.5 22.5 22.5 Lactic acid 37.5 37.5 37.5 37.5 37.537.5 TOTAL 750 750 750 750 750 750 Ratio FAE to Fill 0.74 0.83 0.92 1.031.07 1.14 Percent Weight (%) Fumarate Ester PSD: d90 ≤ 100 μm 56 57.157.6 58.7 61.3 64 Capmul ® MCM 26 24.9 24.4 23.3 20.7 18 Cremophor ® RH40 10 10 10 10 10 10 Povidone K 30 3 3 3 3 3 3 Lactic acid 5 5 5 5 5 5TOTAL 100 100 100 100 100 100

Example 19

Fill compositions having one or more fumarate esters (e.g., dimethylfumarate, monomethyl fumarate, or a combination thereof ranging fromabout 0.5 mmol to about 3.5 mmol) having a particle size distribution ofPSD: d90≤100 μm with a constant weight ratio of fumarate ester to fill(e.g., about 0.40) are shown in Table 32. Millimole values for DMF orMMF (shaded rows) specify the millimoles of the respective species atthe specified mass (mg). These fill compositions may be encapsulated bya soft capsule shell composition as described herein. In one embodiment,the fumarate ester comprises DMF. In another embodiment, the fumarateester comprises MMF. In another embodiment, the fumarate ester comprisesMMF, DMF, or a combination thereof.

TABLE 32 Fumarate Ester Fill Compositions Percent Weight (%) mg/capsuleIngredient EX1-EX4 EX1 EX2 EX3 EX4 Fumarate Ester 28.5 80 85 160 170PSD: d90 ≤ 100 μm mmol DMF N/A 0.56 0.59 1.11 1.18 mmol MMF N/A 0.610.65 1.23 1.31 Capmul ® MCM 53.5 150 159 300 318 Cremophor ® 10 28 29.856 59.5 RH 40 Povidone K 30 3 8.4 8.9 16.8 17.9 Lactic acid 5 14 14.9 2829.8 TOTAL 100 280 298 560 595 Percent Weight (%) mg/capsule IngredientEX5-EX8 EX5 EX6 EX7 EX8 Fumarate Ester 28.5 90 95 180 190 PSD: d90 ≤ 100μm mmol DMF N/A 0.62 0.66 1.25 1.32 mmol MMF N/A 0.69 0.73 1.38 1.46Capmul ® MCM 53.5 169 178 337 356 Cremophor ® 10 31.5 33.3 63 66.5 RH 40Povidone K 30 3 9.5 10 18.9 20 Lactic acid 5 15.8 16.6 31.5 33.3 TOTAL100 315 333 630 665 Percent Weight (%) mg/capsule Ingredient EX9-EX12EX9 EX10 EX11 EX12 Fumarate Ester 28.5 100 107 200 214 PSD: d90 ≤ 100 μmmmol DMF N/A 0.69 0.74 1.39 1.48 mmol MMF N/A 0.77 0.82 1.4 1.64Capmul ® MCM 53.5 187 201 375 401 Cremophor ® 10 35 37.5 70.1 75 RH 40Povidone K 30 3 10.5 11.3 21 22.5 Lactic acid 5 17.5 18.8 35.1 37.5TOTAL 100 350 375 701 750 Percent Weight (%) mg/capsule IngredientEX13-EX16 EX17 EX18 EX19 EX20 Fumarate Ester 28.5 105 110 210 220 PSD:d90 ≤ 100 μm mmol DMF N/A 0.73 0.76 1.46 1.3 mmol MMF N/A 0.81 0.85 1.611.69 Capmul ® MCM 53.5 197 206 393 412 Cremophor ® 10 36.8 38.5 73.577.0 RH 40 Povidone K 30 3 11.0 11.6 22.1 23.1 Lactic acid 5 18.4 19.336.8 38.5 TOTAL 100 368 385 735 770 Percent Weight (%) mg/capsuleIngredient EX13-EX16 EX17 EX18 EX19 EX20 Fumarate Ester 28.5 115 120 230240 PSD: d90 ≤ 100 μm mmol DMF N/A 0.80 0.83 1.60 1.67 mmol MMF N/A 0.880.92 1.77 1.84 Capmul ® MCM 53.5 215 225 431 449 Cremophor ® 10 40.342.0 80.5 84.0 RH 40 Povidone K 30 3 12.1 12.6 24.2 25.2 Lactic acid 520.1 21.0 40.3 42.0 TOTAL 100 403 420 805 840 Percent Weight (%)mg/capsule Ingredient EX13-EX16 EX13 EX14 EX15 EX16 Fumarate Ester 28.5350 375 400 428 PSD: d90 ≤ 100 μm mmol DMF N/A 2.42 2.6 2.78 2.97 mmolMMF N/A 2.68 2.88 3.07 3.29 Capmul ® MCM 53.5 655 702 750 802Cremophor ® 10 123 131 140 150 RH 40 Povidone K 30 3 36.8 39.4 42.1 45Lactic acid 5 61.3 65.6 70.1 75 TOTAL 100 1225 1313 1402 1500

Example 20

A batch of enteric soft capsules (0.038-inch shell thickness) comprisingmonomethyl fumarate particles having particle size distribution of PSD:d90≤90 μm were prepared with the matrix composition shown in Table 33.

TABLE 33 Monomethyl Fumarate Fill Composition Fill Ingredients PercentWeight (%) Mass/capsule (mg) Monomethyl fumarate, 28.50 214 PSD: d90 ≤90 μm Capmul ® MCM 53.50 401 Cremophor ® RH 40 10.00 75 Povidone K 303.00 23 Lactic Acid 5.00 38 Total Fill Weight 100% 750 Total CapsuleWeight 1116

Samples from a batch of enteric soft capsules comprising the compositionshown in Table 33 were subject to two-stage dissolution experiments in aUSP Apparatus II with the parameters shown in Table 34. For theseexperiments, the capsule was introduced in to simulated gastric fluid,0.1 N HCl, pH 1.2, for 2 hours. After 2 hours, the capsule wastransferred to simulated intestinal fluid, phosphate buffer, pH 6.8.Samples were removed from the apparatus at the indicated time points andthe analyte was detected using high performance liquid chromatography(HPLC) with a UV detector. The results are shown in FIG. 14. The resultsshow that the capsules retain their enteric properties for at least 2hours in simulated gastric fluid at pH 1.2. The capsules began releasingmonomethyl fumarate within ˜10 minutes after being transferred tosimulated intestinal fluid, pH 6.8, and achieved 100% dissolution after120 minutes at pH 6.8.

TABLE 34 Two-stage Dissolution Analysis Parameters USP Apparatus IIAgitation Rate 100 RPM Temperature 37.0 ± 0.5° C. Media/Volume 0.1N HCl,pH 1.2, 500 mL Phosphate buffer, pH 6.8, 500 mL Sample Profile: Samplesobtained at 60 min and 120 min in 0.1N HCl Samples obtained at 10, 20,30, 45, 60, 120 min in phosphate buffer pH 6.8

Example 21 Method for Measurement of Fumarate Ester Particles SizeDistribution

Fumarate ester particles (dimethyl fumarate or mono methyl fumarate) inthe form of a dry powder were measured using a Malvern Mastersizer 2000instrument equipped with vacuum unit and air pressure followingmanufacturer instructions; see, e.g. The Mastersizer 2000 OperatorsGuide; MAN0247-2-0, Malvern Instruments Ltd. (1999), which isincorporated by reference herein for such teachings. Approximately 1.0gram of the test sample was introduced into the dry powder feeder andmeasured under the parameters shown in Table 35, and the volume sizedistribution and the volume mean diameter were determined. In oneaspect, described herein, the particle size distribution is expressed asa particle volume distribution and the mean particle size of thedistribution is expressed as a volume mean diameter.

TABLE 35 Particle Size Distribution Measurement Parameters AnalysisModel General Purpose Sensitivity Normal Particle RI 1.468 Vibrationfeed rate 60% Dispersive air pressure 1.3 bars Absorption 0.1Measurement time 6 seconds Measurement snaps 6,000 Background time 6seconds Background snaps 6,000 No. of measurements 1 per cycleObscuration 0.5% to 6.0%

Example 22 Clinical Study of Test Pharmaceutical Compositions ComprisingFumarate Esters Patient Population

Non-smoking male or females (n=24) within the age range of 18 to 65years, having a Body Mass Index (BMI) greater than or equal to 18.5kg/m² and less than or equal to 29.9 kg/m² and having given theirwritten informed consent were at the Period-I check-in of the study. Thepatient demographics and number of patients dosed is provided in Table36. They did not have any significant diseases or clinically significantabnormal findings during screening, medical history, physical andclinical examinations, laboratory evaluation, 12-lead ECG recording andvital sign measurement. Female volunteers had a negative pregnancy test.Volunteers who meet all the inclusion and exclusion criteria wereenrolled into the study.

All the subjects willing to participate in the study were screened nomore than 28 days before the first drug administration in order toassess their eligibility by satisfying all of the inclusion andexclusion criteria. During screening, the medical history of thesubjects was elicited and they underwent a general clinical examination,measurement of blood pressure, heart rate, body temperature, respiratoryrate, 12-Lead ECG, clinical laboratory evaluations, immunological testsfor HIV (Human Immunodeficiency Virus), HBsAg (Hepatitis B SurfaceAntigen) and HCV (Hepatitis C Virus), Alcohol screen, Nicotine screenand Screen for drugs of abuse. Urine pregnancy test was performed forall female subjects. Subjects were selected for inclusion in the studyno more than 28 days before the first drug administration.

TABLE 36 Study Population Inclusion Numbers and Parameter InformationNo. Planned for Inclusion 24 Enrolled and Checked-in 34 (Subject Nos.1001-1024 and 10 standby subjects) Dosed Period-I 24 Period-II 23 (7days later) Dismissed 01 Analyzed 23 Considered for 23 statisticalanalysis Dosed Completed Parameters Subjects (24) Study (23) Age (years)42.2 ± 12.81 42.2 ± 13.10 Height (cm) 171.14 ± 8.668  171.32 ± 8.817 Weight (kg) 75.05 ± 10.135 75.35 ± 10.258 BMI (kg/m²) 25.55 ± 2.280 25.60 ± 2.320 

Study Methodology

The performed study was a randomized, pilot, two-way crossover,open-label, single-dose, fasting study, with a screening period of28-days prior to the first dose administration. In each study period, 19blood samples, including one pre-dose blood sample, were collected fromeach subject except for the subject who did not complete the study toanalyze the pharmacokinetic profile of the Test pharmaceuticalcomposition as well as the Reference pharmaceutical product.

Based on the elimination half-life of dimethyl fumarate, a washoutperiod of 7-days was kept in between the successive dosing days.Multiple blood samples were collected to assess the bioequivalencebetween the Test and the Reference product. For this study with acrossover design, each subject except for one dismissed subject receivedboth the products (Test Product-T and Reference Product-R) during thestudy. Hence, every subject acted as his own control and no separategroup of subjects was required to act as the control group. Subjectswere dosed according to the treatment sequence provided in Table 37. Theduration of the clinical part of the study was about 9 days (one dayprior to the drug administration in Period-I until the last studyprocedure in Period-II).

TABLE 37 Treatment Sequence Period-I Period-II Sequence 1 Treatment-R(Reference) Treatment-T (Test) Sequence 2 Treatment-T (Test) Treatment-R(Reference)

After an overnight fast of at least 10 hours, a single oral dose (240mg) of a Test controlled release pharmaceutical composition comprising afumarate ester or a Reference dimethyl fumarate composition wasadministered to the subjects in sitting posture with 240 mL of drinkingwater at ambient temperature. The administration was as per therandomization schedule and under open-label conditions.

Dosing water was measured and poured into individual containers beforedosing. The containers were then covered and allowed to remain atambient temperature until used. The drug was provided to the subjects inunit-dose containers. A visual inspection of each subject's mouth andhands was performed immediately after dosing to ensure drug ingestion.

During the first 4-hours post-dose, subjects were encouraged to stayawake, seated in an upright position, and allowed to rise undersupervision only for brief periods of time, in order to comply withstudy-related activities and to use the washroom. Subjects werepermitted to lie down for treatment of any adverse event.

No water ingestion was permitted from 1.0-hour pre-dose to 1.0-hourpost-dose, with the exception of the 240 mL of dosing water.

No food was allowed for at least 4 hours' post-dose. Standardized mealswith beverages were provided to the subjects at the following times:between 4.5- and 5.5-hours post-dose; between 9.5- and 10.5-hourspost-dose; and at 13.5-hours post-dose.

All meals and beverages were free of alcohol, grapefruit products,xanthine, and caffeine and were identical between the study periods.

Safety was assessed from the screening period to the end of the study.It was assessed through clinical examinations, vital signs assessment,12-lead electrocardiogram (ECG), clinical laboratory parameters (e.g.,biochemistry, hematology, immunology, and urine analysis), pregnancytest (for female subjects), subjective symptomatology, and monitoring ofadverse events.

A total of 19 pharmacokinetic blood samples (6 mL each) were drawn ineach period according to the following schedule: 0 (pre-dose), and atintervals of 0.33, 0.67, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3,3.33, 3.68, 4, 4.5, 5, 6, and 8-hours post-dose.

The plasma samples of subjects were analyzed using a validated LC-MS/MSmethod for monomethyl fumarate. Calibration curve using an 8-pointcalibration curve standards, with concentrations ranging from 21.35ng/mL to 4967.75 ng/mL were used to determine the concentrations ofmonomethyl fumarate in the samples of various subjects.

Pharmacokinetic Parameter Calculations

The pharmacokinetic parameters were calculated from the drugconcentration versus time point by non-compartmental model usingWinNonlin Professional Software Version 5.3 (Pharsight Corporation) formonomethyl fumarate. Statistical comparison of the pharmacokineticparameters of the two products (Test, Reference) was performed usingPROC MIXED of SAS® Version 9.3 (SAS Institute Inc.).

The maximum measured plasma concentration (C_(max)) and the time ofobserving the peak concentration (T_(max)) was taken directly from theplasma concentration versus time profile of the individual subjects.

Area under plasma concentration versus time curve (AUC_(0→τ)) in h·ng/mLfrom time zero to the last measurable concentration as calculated by thelinear trapezoidal rule.

Area under the plasma concentration versus time curve (AUC_(0→∞)) inh·ng/mL from time zero to infinity; whereAUC_(0→∞)=AUC_(0→τ)+C_(t)/λ_(z); C_(t) is the last measurableconcentration and λ_(z) is the terminal rate constant. The AUC_(0→∞) wasthe sum of measurable and extrapolated parts.

First order rate constants associated with the terminal (log-linear)portion of the curve were estimated via linear regression of time versuslog concentration. This parameter was calculated by linear least squaresregression analysis using last three or more non-zero plasmaconcentration values. The units of λ_(z) were hours⁻¹ (1/h).

The terminal half-life was calculated using the formula: 0.693/λ_(z).The unit of t % was hour (h).

The residual area in percentage was determined by the formula:

[(AUC_(0→∞)−AUC_(0→τ))/AUC_(0→∞)]×100.

The pharmacokinetic parameters of monomethyl fumarate for Test Product-Tand Reference Product-R are summarized in Table 38. The mean plasmaconcentration versus time curve over eight hours is shown in FIG. 15.

TABLE 38 Pharmacokinetic Parameters of Monomethyl Fumarate; TestProduct-T and Reference Product-R Mean ± SD (Un-transformed data)Pharmacokinetic Test Reference Parameters Product-T Product-R T_(max)(h) 2.5 (1-5) 2.5 (1-5) C_(max) (ng/mL) 1321.3 ± 618.9   1174.7 ± 433.9 AUC_(0→τ) h · ng/mL 1818.415 ± 532.5886  1907.405 ± 525.7948 AUC_(0→∞)1919.247 ± 533.8147*  2119.693 ± 688.1376{circumflex over ( )} λ_(z)(1/h) 1.323 ± 0.3573*  1.103 ± 0.3930{circumflex over ( )} t_(1/2) (h)0.563 ± 0.1586*  0.864 ± 0.8508{circumflex over ( )} Residual Area in1.799 ± 1.0276*  6.481 ± 14.0612{circumflex over ( )} Percentage *n = 20{circumflex over ( )}n = 22

Statistical Methods

Descriptive statistics were calculated and reported for allpharmacokinetic parameters of monomethyl fumarate. ANOVA, power, andratio analysis for ln-transformed pharmacokinetic parameters C_(max),AUC_(0→τ), and AUC_(0→∞) were calculated and reported for monomethylfumarate. The 90% confidence interval for the ratio of the geometricleast-squares means were calculated for the ln-transformedpharmacokinetic parameters, C_(max), AUC_(0→τ), and AUC_(0→∞) formonomethyl fumarate. All statistical analyses for monomethyl fumaratewere performed using PROC MIXED of SAS® Version 9.3 (SAS Institute Inc.,USA).

The relative bioavailability analysis (e.g., geometric least squaresmeans, ratios, 90% confidence interval, intra subject CV, and power) ofTest Product-T versus Reference Product-R for monomethyl fumarate issummarized in Table 39.

TABLE 39 Relative Bioavailability Results for Monomethyl Fumarate (n =23) Geometric Least Squares Means 90% Intra Pow- Param- Test ReferenceRatio Confidence Subject er eters Product-T Product-R (T/R)% Interval CV(%) (%) C_(max) 1189.160 1102.137 107.9 92.04-126.49 32.1 75.3 AUC_(0→T)1747.744 1847.786  94.6 87.59-102.14 15.2 99.8 AUC_(0→∞) 1875.657*2034.147{circumflex over ( )}  92.2 85.17-99.82  14.3 99.7 *n = 20{circumflex over ( )}n = 22

Example 22 Fumarate Ester Oil Composition

Additional fill formulations were developed comprising oils. Oils suchas soybean oil, mineral oil, and vegetable oil were incorporated intothe fill and tested. Based on the results, batches of soft capsules wereprepared by rotary die encapsulation using the fill compositions shownin Table 40.

TABLE 40 Exemplary Oil Fill Composition Ingredient mg/capsule % weightFumarate Ester (PSD: d90 ≤ 100 μm) 100-250 20-50 Oil (e.g., mineral orvegetable oils) 375-225 45-75 Lactic Acid  0-25 0-5 TOTAL 500 mg 100%

Example 23

Soft capsules comprising particles of dimethyl fumarate, monomethylfumarate, or a combination thereof having particle size distribution ofPSD: d90≤100 μm can be prepared with 750 mg or 500 mg matrix fills asshown in Tables 42 and 43.

TABLE 42 Exemplary Fill Composition Ingredient mg/capsule % weightFumarate Ester (PSD: d90 ≤ 100 μm) 150-375  20-50 Mono- anddi-glycerides 150-375  20-50 Polyvinyl pyrrolidone  5.6-37.5 0.75-5 Polyoxyl 40 Hydrogenated castor oil 5.6-90  0.75-12 Lactic Acid   0-37.50.0-5 TOTAL 750 mg 100%

TABLE 43 Exemplary Fill Composition Ingredient mg/capsule % weightFumarate Ester (PSD: d90 ≤ 100 μm) 100-250  20-50 Mono- anddi-glycerides 100-250  20-50 Polyvinyl pyrrolidone 3.8-25  0.75-5 Polyoxyl 40 Hydrogenated castor oil 3.8-60  0.75-12 Lactic Acid  0-250.0-5 TOTAL 500 mg 100%

Example 24

Soft capsules comprising particles of dimethyl fumarate, monomethylfumarate, or a combination thereof having particle size distributions ofPSD: d90≤100 μm were prepared with 750 mg or 500 mg matrix fills asshown in Tables 44-46.

TABLE 44 Exemplary Fill Composition Ingredient mg/capsule % weightFumarate Ester (PSD: d90 ≤ 100 μm) 214 28.5 Mono- and di-glycerides 40053.5 Polyvinyl pyrrolidone 23 3.0 Polyoxyl 40 Hydrogenated castor oil 7510.5 Lactic Acid 38 5.0 TOTAL 750 mg 100%

TABLE 45 Exemplary Fill Composition Ingredient mg/capsule % weightFumarate Ester (PSD: d90 ≤ 100 μm) 214 28.5 Mono- and di-glycerides 19653.5 Polyvinyl pyrrolidone 15 3.0 Polyoxyl 40 Hydrogenated castor oil 5010.0 Lactic Acid 25 5.0 TOTAL 500 mg 100%

TABLE 46 Exemplary Fill Composition Ingredient mg/capsule % weightFumarate Ester (PSD: d90 ≤ 100 μm) 214 42.8 Oil 261 52.2 Lactic Acid 255.0 TOTAL 500 mg 100%

Example 25

Soft capsules comprising particles of a fumarate ester having particlesize distributions of PSD: d90≤100 μm were prepared with 750 mg or 500mg matrix fills as shown in Tables 47-49. Note that lactic acid isoptional; when lactic acid is omitted, the amount of mono anddi-glycerides (Tables 47-48) or soybean oil (Table 49) is increasedaccordingly.

TABLE 47 Exemplary Fill Composition (750 mg) 11 oblong capsule Componentmg % wt mg % wt mg % wt mg % wt Fumarate Ester (PSD: 100 13.3 107 14.3107.5 14.3 108 14.4 d90 ≤ 100 μm) Mono- and di-glycerides 514 68.5 50767.6 506.5 67.5 506 67.5 Polyvinyl pyrrolidone 23 3.1 23 3.1 23 3.1 233.1 Polyoxyl 40 75 10.0 75 10.0 75 10.0 75 10.0 hydrogenated castor oilLactic acid (optional) 38 5.1 38 5.1 38 5.1 38 5.1 TOTAL 750 100% 750100% 750 100% 750 100% Vehicle 650 87 643 86 642.5 86 642 86 Lipid 61282 605 81 604.5 81 604 81 API 100 13 107 14 107.5 14 108 14 Ratio API:Lipid 6.12 6.12 5.65 5.65 5.62 5.62 5.59 5.59 Ratio API: Vehicle 6.506.50 6.01 6.01 5.98 5.98 5.94 5.94 Fumarate Ester (PSD: 200 26.7 21428.5 215 28.7 216 28.8 d90 ≤ 100 μm) Mono- and di-glycerides 414 55.2400 53.3 399 53.2 398 53.1 Polyvinyl pyrrolidone 23 3.1 23 3.1 23 3.1 233.1 Polyoxyl 40 75 10.0 75 10.0 75 10.0 75 10.0 hydrogenated castor oilLactic acid (optional) 38 5.1 38 5.1 38 5.1 38 5.1 TOTAL 750 100% 750100% 750 100% 750 100% Vehicle 550 73 536 71 535 71 534 71 Lipid 512 68498 66 497 66 496 66 API 200 27 214 29 215 29 216 29 Ratio API: Lipid2.56 2.56 2.33 2.33 2.31 2.31 2.30 2.30 Ratio API: Vehicle 2.75 2.752.50 2.50 2.49 2.49 2.47 2.47

TABLE 48 Exemplary Fill Composition (500 mg) 12 oval capsule Componentmg % wt mg % wt mg % wt mg % wt Fumarate Ester (PSD: 100 20.0 107 21.4107.5 21.5 108 21.6 d90 ≤ 100 μm) Mono- and di-glycerides 310 62.0 30360.6 302.5 60.5 302 60.4 Polyvinyl pyrrolidone 15 3.0 15 3.0 15 3.0 153.0 Polyoxyl 40 50 10.0 50 10.0 50 10.0 50 10.0 hydrogenated castor oilLactic acid (optional) 25 5.0 25 5.0 25 5.0 25 5.0 TOTAL 500 100% 500100% 500 100% 500 100% Vehicle 400 80 393 79 392.5 79 392 78 Lipid 37575 368 74 367.5 74 367 73 API 100 20 107 21 107.5 22 108 22 Ratio API:Lipid 3.75 3.75 3.44 3.44 3.42 3.42 3.40 3.40 Ratio API: Vehicle 4.004.00 3.67 3.67 3.65 3.65 3.63 3.63 Fumarate Ester (PSD: 200 40.0 21442.8 215 43.0 216 43.2 d90 ≤ 100 μm) Mono- and di-glycerides 210 42.0196 39.2 195 39.0 194 38.8 Polyvinyl pyrrolidone 15 3.0 15 3.0 15 3.0 153.0 Polyoxyl 40 50 10.0 50 10.0 50 10.0 50 10.0 hydrogenated castor oilLactic acid (optional) 25 5.0 25 5.0 25 5.0 25 5.0 TOTAL 500 100% 500100% 500 100% 500 100% Vehicle 300 60 286 57 285 57 284 57 Lipid 275 55261 52 260 52 259 52 API 200 40 214 43 215 43 216 43 Ratio API: Lipid1.38 1.38 1.22 1.22 1.21 1.21 1.20 1.20 Ratio API: Vehicle 1.50 1.501.34 1.34 1.33 1.33 1.31 1.31

TABLE 49 Exemplary Fill Composition (500 mg) 12 oval capsule Componentmg % wt mg % wt mg % wt mg % wt Fumarate Ester (PSD: 100 20.0 107 21.4107.5 21.5 108 21.6 d90 ≤ 100 μm) Soybean oil 375 75.0 368 73.6 367.573.5 367 73.4 Lactic acid (optional) 25 5.0 25 5.0 25 5.0 25 5.0 TOTAL500 100% 500 100% 500 100% 500 100% Vehicle 400 80 393 79 392.5 79 39279 Lipid 375 75 368 74 367.5 74 367 73 API 100 20 107 21 107.5 22 108 22Ratio API: Lipid 3.75 3.75 3.44 3.44 3.42 3.42 3.40 3.40 Ratio API:Vehicle 4.00 4.00 3.67 3.67 3.65 3.65 3.63 3.63 Fumarate Ester (PSD: 20040.0 214 42.8 215 43.0 216 43.2 d90 ≤ 100 μm) Soybean oil 275 55.0 26152.2 260 52.0 259 51.8 Lactic acid (optional) 25 5.0 25 5.0 25 5.0 255.0 TOTAL 500 100% 500 100% 500 100% 500 100% Vehicle 300 60 286 57 28557 284 57 Lipid 275 55 261 52 260 52 259 52 API 200 40 214 43 215 43 21643 Ratio API: Lipid 1.38 1.38 1.22 1.22 1.21 1.21 1.20 1.20 Ratio API:Vehicle 1.50 1.50 1.34 1.34 1.33 1.33 1.31 1.31

Example 26 DMF and MMF Enteric Soft Capsule Comparison

Comparisons among enteric soft capsules comprising dimethyl fumarate(DMF) or monomethyl fumarate (MMF) show that about 15% of the MMF isreleased from the enteric soft capsule in acidic media (pH 1.2) incontrast to DMF (FIG. 16). Without being bound to any theory, thisdifference is believed to be due to MMF's increased solubility in thematrix fill and in water. Solid particles of MMF are thought topartially dissolve in the capsule matrix fill and create an osmoticgradient between the fill and the acidic media. Water influx across thegradient into the shell further dissolves MMF and facilitates diffusionof it out of the capsule.

Example 27 Vehicle and Enteric Capsule Shell Analyses

Experiments were conducted to evaluate the effect of the matrix fill ona fumarate ester's release from enteric soft capsules in acidic media.FIG. 17-19 show the release of a fumarate ester from different matrixfills in enteric soft capsules over 180 minutes in pH 1.2 media. FIG. 17shows a fill comprising soybean oil; FIG. 18 shows a fill comprisingmixture of soybean and vegetable oil; and FIG. 19 shows a fillcomprising a mixture of mono- and di-glycerides (e.g., Capmul® MCM).About 23% of the fumarate ester released from the soybean oil fill after180 min. About 15% of the fumarate ester released from the soybean andvegetable oil fill after 180 min. About 25% of the fumarate esterreleased from the soybean oil fill after 180 min.

Example 28 Capsule Analysis

In order to prevent the release of fumarate ester fills from capsules,the effect of coatings was evaluated. Soft capsules and enteric softcapsules were manufactured containing fumarate ester fill matrices(e.g., Tables 44-46). These capsules were then coated with an entericcoating (e.g., aqueous methacrylic acid copolymer (Eudragit® L100-55)and triethyl citrate) and evaluated in two-stage dissolutionexperiments. Typical soft gel capsules (e.g., Table 5), high-Bloom softcapsules (e.g., Table 6), or enteric soft capsules (e.g., Table 8) werecoated and evaluated. FIG. 20 illustrates the average of three two-stagedissolutions of fumarate ester capsules in a coated soft gel capsules ora high-Bloom soft capsules. The enterically coated soft capsulesreleased about 50% of the fumarate ester afer about 30-40 minutes aftertransition to pH 6.8. FIG. 21 illustrates the average of three two-stagedissolutions of fumarate ester capsules in a coated soft gel capsules,high-Bloom soft capsules, or enteric soft capsules. The entericallycoated enteric soft capsules released about 50% of the fumarate esterafer about 40-50 minutes after transition to pH 6.8. FIG. 22 comparesthe data shown in FIG. 21 with the release of DMF from an enteric softcapsule (as shown in FIG. 16). FIG. 23 compares the effect of apre-coating (aqueous hydroxypropyl methylcellulose) applied prior to theapplication of the enteric coating of typical soft capsules or entericsoft capsules comprising a matrix fill of a fumarate ester. Theenterically coated soft capsules released about 50% of the fumarateester afer about 30-40 minutes after transition to pH 6.8. Theenterically coated enteric soft capsule released about 50% of thefumarate ester after about 40-50 minutes after transition to pH 6.8.

Example 29

Soft capsules comprising particles of fumarate esters (e.g., monomethylfumarate, dimethyl fumarate, or a combination thereof) having particlesize distributions of PSD: d90≤100 μm were prepared with 600 mg, 700 mg,or 800 mg matrix fills as shown in Tables 50-55. Note that lactic acidis optional; when lactic acid is omitted, the amount of mono anddi-glycerides (Tables 50, 52, 54) or soybean oil (Tables 51, 53, 55) isincreased accordingly.

TABLE 50 Exemplary Fill Composition (600 mg) Component mg % wt mg % wtmg % wt mg % wt Fumarate Ester 100 16.7 107 17.8 107.5 17.9 108 18.0(PSD: d90 ≤ 100 μm) Mono-and di-glycerides 392 65.3 385 64.2 384.5 64.1384 64.0 Polyvinyl pyrrolidone 18 3.0 18 3.0 18 3.0 18 3.0 Polyoxyl 4060 10.0 60 10.0 60 10.0 60 10.0 hydrogenated castor oil Lactic acid(optional) 30 5.0 30 5.0 30 5.0 30 5.0 TOTAL 600 100% 600 100% 600 100%600 100% Vehicle 500 83 493 82 492.5 82 492 82 Lipid 470 78 463 77 462.577 462 77 API 100 17 107 18 107.5 18 108 18 Ratio API:Lipid 4.70 4.704.33 4.33 4.30 4.30 4.28 4.28 Ratio API:Vehicle 5.00 5.00 4.61 4.61 4.584.58 4.56 4.56 Fumarate Ester 200 33.3 214 35.7 215 35.8 216 36.0 (PSD:d90 ≤ 100 μm) Mono-and di-glycerides 292 48.7 278 46.3 277 46.2 276 46.0Polyvinyl pyrrolidone 18 3.0 18 3.0 18 3.0 18 3.0 Polyoxyl 40 60 10.0 6010.0 60 10.0 60 10.0 hydrogenated castor oil Lactic acid (optional) 305.0 30 5.0 30 5.0 30 5.0 TOTAL 600 100% 600 100% 600 100% 600 100%Vehicle 400 67 386 64 385 64 384 64 Lipid 370 62 356 59 355 59 354 59API 200 33 214 36 215 36 216 36 Ratio API:Lipid 1.85 1.85 1.66 1.66 1.651.65 1.64 1.64 Ratio API:Vehicle 2.00 2.00 1.80 1.80 1.79 1.79 1.78 1.78

TABLE 51 Exemplary Fill Composition (600 mg) Component mg % wt mg % wtmg % wt mg % wt Fumarate Ester 100 16.7 107 17.8 107.5 17.9 108 18.0(PSD: d90 ≤ 100 μm) Soybean oil 470 78.3 463 77.2 462.5 77.1 462 77.0Lactic acid (optional) 30 5.0 30 5.0 30 5.0 30 5.0 TOTAL 600 100% 600100% 600 100% 600 100% Vehicle 500 83 493 82 492.5 82 492 82 Lipid 47078 463 77 462.5 77 462 77 API 100 17 107 18 107.5 18 108 18 RatioAPI:Lipid 4.70 4.70 4.33 4.33 4.30 4.30 4.28 4.28 Ratio API:Vehicle 5.005.00 4.61 4.61 4.58 4.58 4.56 4.56 Fumarate Ester 200 33.3 214 35.7 21535.8 216 36.0 (PSD: d90 ≤ 100 μm) Soybean oil 370 61.7 356 59.3 355 59.2354 59.0 Lactic acid (optional) 30 5.0 30 5.0 30 5.0 30 5.0 TOTAL 600100% 600 100% 600 100% 600 100% Vehicle 400 67 386 64 385 64 384 64Lipid 370 62 356 59 355 59 354 59 API 200 33 214 36 215 36 216 36 RatioAPI:Lipid 1.85 1.85 1.66 1.66 1.65 1.65 1.64 1.64 Ratio API:Vehicle 2.002.00 1.80 1.80 1.79 1.79 1.78 1.78

TABLE 52 Exemplary Fill Composition (700 mg) Component mg % wt mg % wtmg % wt mg % wt Fumarate Ester 100 14.3 107 15.3 107.5 15.4 108 15.4(PSD: d90 ≤ 100 μm) Mono-and di-glycerides 474 67.7 467 66.7 466.5 66.6466 66.6 Polyvinyl pyrrolidone 21 3.0 21 3.0 21 3.0 21 3.0 Polyoxyl 4070 10.0 70 10.0 70 10.0 70 10.0 hydrogenated castor oil Lactic acid(optional) 35 5.0 35 5.0 35 5.0 35 5.0 TOTAL 700 100% 700 100% 700 100%700 100% Vehicle 600 86 593 85 592.5 85 592 85 Lipid 565 81 558 80 557.580 557 80 API 100 14 107 15 107.5 15 108 15 Ratio API:Lipid 5.65 5.655.21 5.21 5.19 5.19 5.16 5.16 Ratio API:Vehicle 6.00 6.00 5.54 5.54 5.515.51 5.48 5.48 Fumarate Ester 200 28.6 214 30.6 215 30.7 216 30.9 (PSD:d90 ≤ 100 μm) Mono-and di-glycerides 374 53.4 360 51.4 359 51.3 358 51.1Polyvinyl pyrrolidone 21 3.0 21 3.0 21 3.0 21 3.0 Polyoxyl 40 70 10.0 7010.0 70 10.0 70 10.0 hydrogenated castor oil Lactic acid (optional) 355.0 35 5.0 35 5.0 35 5.0 TOTAL 700 100% 700 100% 700 100% 700 100%Vehicle 500 71 486 69 485 69 484 69 Lipid 465 66 451 64 450 64 449 64API 200 29 214 31 215 31 216 31 Ratio API:Lipid 2.33 2.33 2.11 2.11 2.092.09 2.08 2.08 Ratio API:Vehicle 2.50 2.50 2.27 2.27 2.26 2.26 2.24 2.24

TABLE 53 Exemplary Fill Composition (700 mg) Component mg % wt mg % wtmg % wt mg % wt Fumarate Ester 100 14.3 107 15.3 107.5 15.4 108 15.4(PSD: d90 ≤ 100 μm) Soybean oil 565 80.7 558 79.7 557.5 79.6 557 79.6Lactic acid (optional) 35 5.0 35 5.0 35 5.0 35 33.0 TOTAL 700 100% 700100% 700 100% 700 100% Vehicle 600 86 593 85 592.5 85 592 113 Lipid 56581 558 80 557.5 80 557 80 API 100 14 107 15 107.5 15 108 15 RatioAPI:Lipid 5.65 5.65 5.21 5.21 5.19 5.19 5.16 5.16 Ratio API:Vehicle 6.006.00 5.54 5.54 5.51 5.51 5.48 7.30 Fumarate Ester 200 28.6 214 30.6 21530.7 216 30.9 (PSD: d90 ≤ 100 μm) Soybean oil 465 66.4 451 64.4 450 64.3449 64.1 Lactic acid (optional) 35 5.0 35 5.0 35 5.0 35 5.0 TOTAL 700100% 700 100% 700 100% 700 100% Vehicle 500 71 486 69 485 69 484 69Lipid 465 66 451 64 450 64 449 64 API 200 29 214 31 215 31 216 31 RatioAPI:Lipid 2.33 2.33 2.11 2.11 2.09 2.09 2.08 2.08 Ratio API:Vehicle 2.502.50 2.27 2.27 2.26 2.26 2.24 2.24

TABLE 54 Exemplary Fill Composition (800 mg) Component mg % wt mg % wtmg % wt mg % wt Fumarate Ester 100 12.5 107 15.3 107.5 13.4 108 13.5(PSD: d90 ≤ 100 μm) Mono-and di-glycerides 556 69.5 549 68.6 548.5 68.6548 68.5 Polyvinyl pyrrolidone 24 3.0 24 3.0 24 3.0 24 3.0 Polyoxyl 4080 10.0 80 10.0 80 10.0 80 10.0 hydrogenated castor oil Lactic acid(optional) 40 5.0 40 5.0 40 5.0 40 5.0 TOTAL 800 100% 800 100% 800 100%800 100% Vehicle 700 88 693 87 692.5 87 692 87 Lipid 660 83 653 82 652.582 652 82 API 100 13 107 15 107.5 13 108 14 Ratio API:Lipid 6.60 6.606.10 5.34 6.07 6.07 6.04 6.04 Ratio API:Vehicle 7.00 7.00 6.48 5.67 6.446.44 6.41 6.41 Fumarate Ester 200 25.0 214 26.8 215 26.9 216 27.0 (PSD:d90 ≤ 100 μm) Mono-and di-glycerides 456 57.0 442 55.3 441 55.1 440 55.0Polyvinyl pyrrolidone 24 3.0 24 3.0 24 3.0 24 3.0 Polyoxyl 40 80 10.0 8010.0 80 10.0 80 10.0 hydrogenated castor oil Lactic acid (optional) 405.0 40 5.0 40 5.0 40 5.0 TOTAL 800 100% 800 100% 800 100% 800 100%Vehicle 600 75 586 73 585 73 584 73 Lipid 560 70 546 68 545 68 544 68API 200 25 214 27 215 27 216 27 Ratio API:Lipid 2.80 2.80 2.55 2.55 2.532.53 2.52 2.52 Ratio API:Vehicle 3.00 3.00 2.74 2.74 2.72 2.72 2.70 2.70

TABLE 55 Exemplary Fill Composition (800 mg) Component mg % wt mg % wtmg % wt mg % wt Fumarate Ester 100 12.5 107 13.4 107.5 13.4 108 13.5(PSD: d90 ≤ 100 μm) Soybean oil 660 82.5 653 81.6 652.5 81.6 652 81.5Lactic acid (optional) 40 5.0 40 5.0 40 5.0 40 5.0 TOTAL 800 100% 800100% 800 100% 800 100% Vehicle 700 88 693 87 692.5 87 692 87 Lipid 66083 653 82 652.5 82 652 82 API 100 13 107 13 107.5 13 108 14 RatioAPI:Lipid 6.60 6.60 6.10 6.10 6.07 6.07 6.04 6.04 Ratio API:Vehicle 7.007.00 6.48 6.48 6.44 6.44 6.41 6.41 Fumarate Ester 200 25.0 214 26.8 21526.9 216 27.0 (PSD: d90 ≤ 100 μm) Soybean oil 560 70.0 546 68.3 545 68.1544 68.0 Lactic acid (optional) 40 5.0 40 5.0 40 5.0 40 5.0 TOTAL 800100% 800 100% 800 100% 800 100% Vehicle 600 75 586 73 585 73 584 73Lipid 560 70 546 68 545 68 544 68 API 200 25 214 27 215 27 216 27 RatioAPI:Lipid 2.80 2.80 2.55 2.55 2.53 2.53 2.52 2.52 Ratio API:Vehicle 3.003.00 2.74 2.74 2.72 2.72 2.70 2.70

Example 30

Soft capsules comprising particles of fumarate esters (e.g., monomethylfumarate, dimethyl fumarate, or a combination thereof) having particlesize distributions of PSD: d90≤100 μm were prepared with 625 mg, matrixfills as shown in Tables 56-57.

TABLE 56 Exemplary Fill Composition (625 mg) Component mg % wt mg % wtmg % wt mg % wt Fumarate Ester 100 16.0 107 17.1 107.5 17.2 108 17.3(PSD: d90 ≤ 100 μm) Mono-and di-glycerides 412.5 66.0 405.5 64.9 40564.8 404.5 64.7 Polyvinyl pyrrolidone 18.8 3.0 18.8 3.0 18.8 3.0 18.83.0 Polyoxyl 40 62.5 10.0 62.5 10.0 62.5 10.0 62.5 10.0 hydrogenatedcastor oil Lactic acid (optional) 31.2 5.0 31.2 5.0 31.2 5.0 31.2 5.0TOTAL 625 100% 625 100% 625 100% 625 100% Vehicle 525 84 518 83 517.5 83517 83 Lipid 493.8 79 486.8 78 486.3 78 485.8 78 API 100 16 107 17 107.517 108 17 Ratio API:Lipid 4.94 4.94 4.55 4.55 4.52 4.52 4.50 4.50 RatioAPI:Vehicle 5.25 5.25 4.84 4.84 4.81 4.81 4.79 4.79 Fumarate Ester 20032.0 214 34.2 215 34.4 216 34.6 (PSD: d90 ≤ 100 μm) Mono-anddi-glycerides 312.5 50.0 298.5 47.8 297.5 47.6 296.5 47.4 Polyvinylpyrrolidone 18.75 3.0 18.75 3.0 18.75 3.0 18.75 3.0 Polyoxyl 40 62.510.0 62.5 10.0 62.5 10.0 62.5 10.0 hydrogenated castor oil Lactic acid(optional) 31.25 5.0 31.25 5.0 31.25 5.0 31.25 5.0 TOTAL 625 100% 625100% 625 100% 625 100% Vehicle 425 68 411 66 410 66 409 65 Lipid 393.863 379.8 61 378.8 61 377.8 60 API 200 32 214 34 215 34 216 35 RatioAPI:Lipid 1.97 1.97 1.77 1.77 1.76 1.76 1.75 1.75 Ratio API:Vehicle 2.132.13 1.92 1.92 1.91 1.91 1.89 1.89

TABLE 57 Exemplary Fill Composition (625 mg) Component mg % wt mg % wtmg % wt mg % wt Fumarate Ester 100 16.0 107 17.1 107.5 17.2 108 17.3(PSD: d90 ≤ 100 μm) Soybean oil 525 84.0 518 82.9 517.5 82.8 517 82.7TOTAL 625 100% 625 100% 625 100% 625 100% Lipid 525 84 518 83 517.5 83517 83 API 100 16 107 17 107.5 17 108 17 Ratio API:Lipid 5.25 5.25 4.844.84 4.81 4.81 4.79 4.79 Fumarate Ester 200 32.0 214 34.2 215 34.4 21634.6 (PSD: d90 ≤ 100 μm) Soybean oil 425 68.0 411 65.8 410 65.6 409 65.4TOTAL 625 100% 625 100% 625 100% 625 100% Lipid 425 68 411 66 410 66 40965 API 200 32 214 34 215 34 216 35 Ratio API:Lipid 2.13 2.13 1.92 1.921.91 1.91 1.89 1.89

Example 31

Soft capsules comprising particles of a fumarate ester having particlesize distributions of PSD: d90≤100 μm were manufactured for clinicalinvestigations. Six different formulations were prepared. See Table 58.The dosage forms comprised two different doses of fumarate ester, twodifferent fill formulations, and two different shell components. Thedoses were either 200 mg or 214 mg of fumarate ester and the fillformulations either comprised a mixture of mono- and di-glycerides(e.g., Capmul® MCM) or soybean oil. Tables 59-64. The soft capsules wereeither an enteric soft capsule (EnteriCare®, Banner Life Sciences) orsoft gelatin capsules. See Tables 65-66. Both types of capsules weremanufactured using rotary die encapsulation.

After manufacturing and drying, the capsules were coated with ahydroxypropylmethylcellulose undercoat and dried. The capsules were thencoated with an enteric coating containing methacrylic acid, ethylacrylate copolymer (e.g., EUDRAGIT® L100-55, Evonik; Acryl-EZE®,Colorcon). Table 67. Finally, a polyvinyl alcohol moisture barriertop-coating was applied to the enterically coated capsules (e.g.,Opadry® amb II, Clear, Colorcon). Table 68.

TABLE 58 Summary of Clinical Investigation Formulations Test 1 Test 2Test 3 Test 4 Test 5 Test 6 Fumarate 214 200 214 214 200 214 Ester Dose(mg) Formulation Capmul Capmul Capmul Soybean Soybean Soybean oil oiloil Shell Enteric Enteric Softgel Enteric Enteric Softgel SGC SGC SGCSGC

TABLE 59 Test 1 Formulation Component Mass (mg) Weight % Fumarate Ester214.0 34.2 Capmul ® MCM 298.5 47.8 Povidone K30 18.8 3.0 Polyoxyl 40Hydrogenated Castor Oil 62.5 10.0 Lactic Acid 31.2 5.0 TOTAL 625.0 100%

TABLE 60 Test 2 Formulation Component Mass (mg) Weight % Fumarate Ester200.0 34.2 Capmul ® MCM 279.0 47.8 Povidone K30 17.5 3.0 Polyoxyl 40Hydrogenated Castor Oil 58.4 10.0 Lactic Acid 29.2 5.0 TOTAL 584.3 100%

TABLE 61 Test 3 Formulation Component Mass (mg) Weight % Fumarate Ester214.0 34.2 Capmul MCM 298.5 47.8 Povidone K30 18.8 3.0 Polyoxyl 40Hydrogenated Castor Oil 62.5 10.0 Lactic Acid 31.2 5.0 TOTAL 625.0 100%

TABLE 62 Test 4 Formulation Component Mass (mg) Weight % Fumarate Ester214.0 34.2 Soybean oil 411.0 65.8 TOTAL 625.0 100%

TABLE 63 Test 5 Formulation Component Mass (mg) Weight % Fumarate Ester200.0 34.2 Soybean oil 384.0 65.8 TOTAL 584.0 100%

TABLE 64 Test 6 Formulation Component Mass (mg) Weight % Fumarate Ester214.0 34.2 Soybean oil 411.0 65.8 TOTAL 625.0 100%

TABLE 65 EnteriCare ® Enteric soft capsule shell composition ComponentMass (g) Weight % Gelatin, 150 Bloom 116.6 27.3 Methacrylic AcidCopolymer Type A 44.6 10.5 Ammonium Hydroxide 6.9 1.6 Glycerin 72.2 16.9Triethyl Citrate 5.0 1.2 Purified water 180.2 42.2 Titanium Dioxide0.867 0.20 FD&C Blue #1 0.213 0.05 TOTAL 426.6 100.0%

TABLE 66 Soft capsule shell composition Component Mass (g) Weight %Gelatin, 195 Bloom 172.4 52.2 Polysorb ® 85/70/00 (D-Sorbitol/sorbitans)99.0 30.0 Purified water 58.0 17.6 Titanium Dioxide 0.8 0.24 FD&C Blue#1 0.2 0.06 TOTAL 330.4 100.0%

TABLE 67 Enteric Coating Composition (Acryl-EZE ®, Colorcon) ComponentMass (g) Weight % Methacrylic acid, ethyl acrylate 1826 86.6 copolymerTalc Triethyl citrate Sodium bicarbonate Colloidal anhydrous silicaSodium lauryl sulfate Triethyl citrate* 233.8 11.4 Water† 8236 399.8TOTAL 2059.8 100.0% *Additional triethyl citrate added. †A majority ofthe water evaporates during the coating process.

TABLE 68 Moisture Barrier Top Coating Composition (Opadry ® amb II,Clear; Colorcon) Component Mass (g) Weight % Polyvinyl alcohol 600 10.0Glyceryl mono-caprylate-caprate Sodium lauryl sulfate Talc TitaniumDioxide Water* 5400 90.0 TOTAL 6000 100.0% *A majority of the waterevaporates during the coating process.

Example 32

A single-dose, randomized, open-label, 4-way crossover, pilotcomparative bioavailability study of a delayed-release fumarate ester ata dose of 200 mg and 214 mg in capsules and TECFIDERA® 240 mg dimethylfumarate (DMF) delayed-release capsules in healthy male and femalevolunteers under fasting conditions was performed. This pilot studyassessed the tolerability, pharmacokinetics and comparativebioavailability of the fumarate ester in three test formulations and attwo dose strengths (200 mg and 214 mg delayed-release capsules) and onereference drug, TECFIDERA® (dimethyl fumarate; Biogen) 240 mgdelayed-release capsules, in healthy male and female volunteers underfasting conditions. A sample size of 24 subjects was selected for thisstudy. The study population included healthy, non-smoking, male andnon-pregnant female volunteers, 18 years of age or older, with a bodymass index (BMI) within 18.5-29.9 kg/m², inclusive.

Six investigational formulations of a fumarate ester in delayed-releasesoft capsules were evaluated. Three of these formulations comprise mono-and di-glycerides (e.g., Capmul® MCM; Test Samples 1-3) and threecomprise soybean oil (Test Samples 4-6). Two dose strengths, 200 mg(Tests 2 and 5) and 214 mg of fumarate ester (Tests 1, 3, 4 6), weremanufactured using the mono- and di-glyceride and soybean oil-basedformulations described herein in Example 31. Additionally, two differentsoft capsule shell formulations were evaluated on the higher (214 mg)test formulations as indicated by the labels EnteriCare® (enteric softcapsule; Tests 1, 2, 4, 5) and 195 bloom (195-Bloom gelatin soft capsulethat is enterically coated; Tests 3 and 6). The relative bioavailabilityof the three mono- and di-glyceride-based formulations was assessedagainst the reference listed drug (RLD), TECFIDERA® (dimethyl fumarate;Biogen), delayed-release oral capsule, 240 mg, manufactured by Biogen,Inc. A companion study assessed the soybean oil-based formulationsagainst TECFIDERA®. These studies were conducted to evaluateformulations and dose strengths that are bioequivalent to TECFIDERA® 240mg, and to evaluate the tolerability, including the incidence offlushing and gastrointestinal side effects, of a fumarate ester whenadministered to healthy subjects.

TECFIDERA® (dimethyl fumarate) is indicated for the treatment ofpatients with relapsing forms of multiple sclerosis. See TECFIDERA®product label, incorporated by reference herein for such teachings.

The mechanism by which dimethyl fumarate (DMF) exerts its therapeuticeffect in multiple sclerosis is unknown. DMF and its metabolite,monomethyl fumarate (MMF), activate the Nuclear factor(erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo inanimals and humans. The Nrf2 pathway is involved in the cellularresponse to oxidative stress. MMF has been identified as a nicotinicacid receptor agonist in vitro.

After oral administration of TECFIDERA®, dimethyl fumarate undergoesrapid presystemic hydrolysis by esterases and is converted to its activemetabolite, monomethyl fumarate (MMF). Dimethyl fumarate is notquantifiable in plasma following oral administration of TECFIDERA®.Pharmacokinetic analyses related to TECFIDERA® were performed byevaluating plasma MMF concentrations. Pharmacokinetic data were obtainedin subjects with multiple sclerosis and healthy volunteers.

The median T_(max) of MMF is 2-2.5 hours. The peak plasma concentration(C_(max)) and overall exposure (AUC_(overall)) increased approximatelydose proportionally in the dose range studied (120 mg to 360 mg).Following administration of TECFIDERA® 240 mg twice a day with food, themean C_(max) of MMF was 1.87 mg/L and AUC_(overall) was 8.21 mg·hr/L inMS patients.

A high-fat, high-calorie meal did not affect the AUC of MMF butdecreased its C_(max) by 40%; the T_(max) was delayed from 2.0 hours to5.5 hours. The incidence of flushing was reduced by approximately 25% inthe fed state.

The apparent volume of distribution of MMF varies between 53 and 73 L inhealthy subjects. Human plasma protein binding of MMF is 27-45% andindependent of concentration.

In humans, dimethyl fumarate is extensively metabolized by esterases,which are ubiquitous in the gastrointestinal tract, blood, and tissues,before DMF reaches the systemic circulation. Further metabolism of MMFoccurs through the tricarboxylic acid (TCA) cycle, with no involvementof the cytochrome P450 (CYP) system. MMF, fumaric acid, citric acid, andglucose are the major metabolites detectable in plasma.

Exhalation of CO₂ is the primary route of elimination, accounting forapproximately 60% of the TECFIDERA® DMF dose. Renal and fecal are minorelimination routes, accounting for 16% and 1% of the dose, respectively.Trace amounts of MMF were present in urine.

The terminal half-life of MMF is approximately 1 hour and no circulatingMMF is present at 24 hours in the majority of individuals. Accumulationof MMF does not occur with multiple doses of TECFIDERA®.

This study was conducted in normal healthy male and non-pregnant femalevolunteers. This was a single-dose, randomized, open-label, 4-waycrossover, four-period, four-sequence, four-treatment, single-center,comparative bioavailability study of three formulations of a fumarateester at doses of 214 mg and 200 mg in delayed-release capsules andTECFIDERA® (dimethyl fumarate) 240 mg delayed-release capsules (Biogen,Inc.). The formulations were studied using a crossover design with 24healthy, non-smoking male and non-pregnant female volunteers beingadministered an oral dose of 1×214 mg, 1×200 mg, or 1×240 mgdelayed-release capsule under fasting conditions. There was at least a2-day washout period between the study periods. The washout period of atleast 2 days was estimated to be adequate in avoiding carry-over effectsof the preceding treatments.

Blood samples were obtained by direct venipuncture in the arm andcollected in pre-chilled sodium fluoride/potassium oxalate 6 mLVacutainers®. Blood sample collection times were recorded on theappropriate source documents and reported for each subject. Bloodsamples were collected at pre-dose (0 hour), and at 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12 and 24-hours post-dose in each studyperiod.

Subjects were confined to the clinic from at least 10-hours prior todosing until at least 24-hours post-dose in Period 4, for a total of atleast 178 hours (approximately 8 days) in the study.

The assignment of treatment groups (randomization scheme) was generatedby a computer program designed and run in SAS® Version 9.4. This was anopen-label study and subjects as well as clinic staff were not blindedto the randomization. The analytical laboratory did not have access tothe randomization scheme until the bioanalytical analyses werecompleted.

Subjects who meet the eligibility criteria were randomly assigned toreceive the study drugs according to one of the four dosing sequences:

Period 1 Period 2 Period 3 Period 4 Sequence 1 T1 T2 T3 R Sequence 2 T2T3 R T1 Sequence 3 T3 R T1 T2 Sequence 4 R T1 T2 T3Each subject was scheduled to have received a total of four treatmentsby the end of the study.

The treatment labeling scheme was as follows:

Treatment Code T1 (Test) T2 (Test) T3 (Test) R (Reference) Drug Name:Fumarate Ester Fumarate Ester Fumarate Ester TECFIDERA ® (dimethylfumarate) Strength: 214 mg 200 mg 214 mg 240 mg Dosage Form:EnteriCare ® DR EnteriCare ® DR 195 Bloom DR Delayed-release SoftCapsules Soft Capsules Soft Capsules Capsules Manufacturer BLS BLS BLSBiogen Dose: 1 × 214 mg 1 × 200 mg 1 × 214 mg 1 × 240 mg Fill Capmul,Capmul, Capmul, Table 59 Table 60 Table 61 Treatment Code T4 (Test) T5(Test) T6 (Test) R (Reference) Drug Name: Fumarate Ester Fumarate EsterFumarate Ester TECFIDERA ® (dimethyl fumarate) Strength: 214 mg 200 mg214 mg 240 mg Dosage Form: EnteriCare ® DR EnteriCare ® DR 195 Bloom DRDelayed-release Soft Capsules Soft Capsules Soft Capsules CapsulesManufacturer BLS BLS BLS Biogen Dose: 1 × 214 mg 1 × 200 mg 1 × 214 mg 1× 240 mg Fill Soybean oil, Soybean oil, Soybean oil, Table 62 Table 63Table 64

Pharmacokinetic parameters were calculated using non-compartmentalanalysis (NCA) method using SAS® Version 9.4. The followingpharmacokinetic parameters were estimated (where possible) formonomethyl fumarate and included in the pharmacokinetic and statisticalanalysis for the subjects in the final data set:

-   -   C_(max): The maximal observed plasma concentration.    -   T_(max): Time when the maximal plasma concentration is observed.    -   AUC_(0→τ): Area under the concentration-time curve from time        zero until the last measurable concentration or last sampling        time τ, whichever occurs first. AUC_(0→τ)is estimated using the        trapezoidal method.    -   AUC_(0→∞): Area under the concentration-time curve from time        zero to infinity, calculated as AUC_(0→τ)+C_(last)/λ, where        C_(last) is the last measurable concentration.    -   λ: Terminal elimination rate constant, estimated by linear        regression analysis of the terminal portion of the natural log        of concentration (In-concentration) vs. time plot.    -   t_(1/2): Terminal elimination half-life, estimated as ln(2)/λ.

During pharmacokinetic and statistical analyses, drug concentrationsbelow the lower limit of quantitation of the assay were considered aszero prior to the first measurable concentration. Drug concentrationsthat were below the limit of quantitation following a measurable resultwere considered as missing during pharmacokinetic calculations andestimations.

Missed samples and non-reportable concentrations (e.g. quantity notsufficient) from the analytical laboratory were treated in thepharmacokinetic analysis as if they had not been scheduled forcollection.

The λ, t_(1/2), and AUC_(0→∞) parameters were not estimated for plasmaconcentration-time profiles where the terminal linear phase was notclearly defined (R<0.8).

Descriptive statistics (min., max., median, mean, standard deviation,and coefficient of variability) of all pharmacokinetic parameters werecalculated for monomethyl fumarate for the Test and Reference products.

ANOVA including sequence, subjects nested within sequence, period andtreatment were performed on the ln-transformed data for AUC_(0→τ),AUC_(0→∞), and C_(max) and on the untransformed data for T_(max), λ, andt_(1/2). T_(max) was analyzed using an additional non-parametric test(Wilcoxon test).

The 90% Confidence Interval of the Test/Reference ratios of geometricmeans for AUC_(0→τ), AUC_(0→∞), and C_(max) was calculated based on theLSMEANS and ESTIMATE of the ANOVA. Additional statistical and alternatetests were performed as necessary.

The number and percentage of subjects with adverse events was tabulatedby body system and preferred term with a breakdown by treatment. Asubject with multiple adverse events within a body system was onlycounted once towards the total of this body system. Adverse events wereanalyzed using descriptive statistics. Similarly, multiple reports ofthe same preferred term adverse events were counted only once at thehighest intensity and greatest attribution to study treatment.Additional statistical and alternate tests were performed as necessary.

Example 33 Comparative Bioavailability Pilot Study Results

Mean plasma monomethyl fumarate concentrations from the bioavailabilitystudy described in Example 32 are shown for Test samples 1-3 in Table 69and Test samples 4-9 in Table 70. The mean plasma monomethyl fumarateconcentration data are plotted in FIGS. 24 and 25, respectively. Thereference drug (Ref) in both studies is for TECFIDERA® (dimethylfumarate) 240 mg delayed-release capsules (Biogen, Inc.).

TABLE 69 Mean Plasma Monomethyl Fumarate Concentration as a Function ofTime after Dosing Samples T1-T3 and Reference Drug Sample: T1 T2 T3 RefConc. Std Conc. Std Conc. Std Conc. Std Time (h) (ng/mL) Dev. (ng/mL)Dev. (ng/mL) Dev. (ng/mL) Dev. Pre-dosing 0.0 0.0 0.0 0.0 0.0 0.0 0.00.0  0.5 0.0 0.0 0.0 0.0 0.0 0.0 138.3 36.4  1.0 415.3 138.1 7.1 21.50.0 0.0 2611.3 716.3  1.5 389.8 117.1 44.5 77.5 453.9 99.7 2421.5 638.9 2.0 191.4 53.6 66.1 114.2 3467.1 732.6 2625.7 827.1  2.5 1386.6 302.3153.0 239.2 3339.1 830.8 2484.6 787.7  3.0 2196.7 463.6 197.1 204.14062.5 977.3 2487.7 705.2  3.5 2124.5 518.7 240.4 218.5 3142.7 903.12279.7 617.4  4.0 1988.8 532.8 450.5 453.0 2548.8 781.8 1686.9 466.4 4.5 2099.3 527.3 635.5 510.2 2583.9 806.4 3169.3 702.5  5.0 2879.4727.4 909.5 488.7 3747.9 866.7 1933.2 543.2  5.5 2204.0 468.8 698.8288.3 2092.5 489.6 1718.4 440.2  6.0 1024.6 251.2 487.4 268.2 1600.8484.2 655.9 167.3  8.0 697.6 182.6 119.9 161.4 218.6 66.7 216.0 50.912.0 79.8 16.3 4.3 15.7 0.0 0.0 59.6 15.3 24.0 0.0 0.0 0.0 0.0 0.0 0.00.0 0.0

TABLE 70 Mean Plasma Monomethyl Fumarate Concentration as a Function ofTime after Dosing Samples T4-T6 and Reference Drug Sample: T4 T5 T6 RefConc. Std Conc. Std Conc. Std Conc. Std Time (ng/mL) Dev. (ng/mL) Dev.(ng/mL) Dev. (ng/mL) Dev. Pre-dosing 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.5 225.6 946.3 1.2 5.6 64.0 194.0 3.6 12.2  1.0 218.5 653.3 13.5 38.7158.4 300.2 295.3 850.7  1.5 189.3 438.7 54.0 88.1 408.9 629.2 371.3561.9  2.0 406.1 597.1 250.8 363.5 860.2 1022.3 720.1 762.4  2.5 489.4469.2 458.6 730.1 848.3 777.0 931.3 879.1  3.0 748.2 952.7 603.0 710.9885.2 751.7 1106.7 897.1  3.5 693.5 660.2 832.2 648.6 905.4 669.8 818.9747.2  4.0 793.5 523.0 817.4 475.4 834.4 733.1 613.5 553.5  4.5 774.9552.3 756.9 412.5 685.7 627.1 495.7 424.8  5.0 864.3 739.8 790.4 671.6533.5 521.5 678.2 921.3  5.5 491.7 475.2 491.9 395.6 295.5 336.3 350.0459.7  6.0 274.6 299.5 300.0 252.0 155.6 189.0 165.4 193.1  8.0 18.950.7 44.3 95.9 6.4 17.6 5.5 12.6 12.0 1.5 7.3 0.0 0.0 0.0 0.0 1.4 6.824.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

Summary pharmacokinetic parameters from the bioavailability studydescribed in Example 32 are shown for Test samples 1-3 in Table 71 andTest samples 4-9 in Table 72.

TABLE 71 Summary of Comparative Bioavailability Analysis for PlasmaMonomethyl Fumarate Randomized, 4-way crossover, open-label,single-dose, fasting design Geometric Mean *Arithmetic Mean (% CV)AUC_(0→T) AUC_(0→∞) C_(max) AUC_(0→T)/ Sample (h · ng/mL) (h · ng/mL)(ng/mL) T_(max) (h)* t_(1/2) (h)* λ_(z) (1/h)* AUC_(0→∞) ^(†) Reference3246.34 3423.77 1784.08 3.00 0.55 1.3022 0.9791 3397.47 3541.61 1874.93(1.00-5.50) (20.99) (18.08) (1.76) (31.42) (31.08) (30.04) Test 12454.38 3078.63 1206.93 5.00 0.85 1.1127 0.9621 2631.29 3543.47 1367.63(2.5-6.00) (95.08) (35.48) (4.66) (39.85) (25.13) (49.77) Test 2 2209.182631.23 1110.01 5.00 0.93 0.9467 0.9377 2344.10 2665.26 1176.70(2.52-6.00) (55.03) (45.76) (6.24) (32.68) (26.01) (34.38) Test 33318.08 3522.37 2004.25 4.00 0.51 1.4526 0.9734 3495.45 3722.36 2140.42(2.00-6.00) (30.61) (20.63) (2.23) (29.89) (25.65) (37.54) Ratio of 90%Intra-subject Geometric Means Confidence CV (T:R) Interval (%) Test 1AUC_(0→T) 75.60 67.42-84.79 23.48 AUC_(0→∞) 89.92  77.35-104.53 22.51C_(max) 67.65 57.59-79.47 33.44 Test 2 AUC_(0→T) 68.05 60.68-76.32 23.48AUC_(0→∞) 76.85 66.17-89.27 22.51 C_(max) 62.22 52.96-73.09 33.44 Test 3AUC_(0→T) 102.21  91.14-114.62 23.48 AUC_(0→∞) 102.88  90.29-117.2322.51 C_(max) 112.3  95.63-131.98 33.44 Reference: TECFIDERA ® (BiogenIdec), 240 mg dimethyl fumarate, enterically coated pellets Test 1: BLS214 mg fumarate ester, Capmul fill, EnteriCare ® DR Soft Capsules; seeTable 59 Test 2, BLS 200 mg fumarate ester Capmul fill, EnteriCare ® DRSoft Capsules; see Table 60 Test 3, BLS 214 mg fumarate ester, Capmulfill, 195 Bloom DR Soft Capsules; see Table 61 *Arithmetic mean (% CV)only ^(†)Median and range only

TABLE 72 Summary of Comparative Bioavailability Analysis for PlasmaMonomethyl Fumarate Randomized, 4-way crossover, open-label,single-dose, fasting design Geometric Mean *Arithmetic Mean (% CV)AUC_(0→T) AUC_(0→∞) C_(max) AUC_(0→T)/ Sample (h · ng/mL) (h · ng/mL)(ng/mL) T_(max) (h)* t_(1/2) (h)* λ_(z) (1/h)* AUC_(0→∞) ^(†) Reference3175.12 3295.42 1975.68 2.85 0.57 1.2587 0.9842 3306.55 3484.62 2111.34(1.02-5.50) (16.97) (17.94) (1.24) (30.72) (29.31) (34.87) Test 43103.71 3258.09 1657.53 4.00 0.50 1.4256 0.9835 3234.00 3478.19 1848.96(0.52-6.00) (22.51) (17.02) (1.27) (30.78) (29.19) (53.77) Test 52722.58 2985.13 1322.51 4.00 0.53 1.3702 0.9830 2878.77 3206.76 1472.19(2.00-5.50) (20.60) (20.61) (1.06) (35.92) (32.27) (47.44) Test 63193.72 3362.08 1774.03 3.00 0.60 1.3789 0.9759 3370.97 3505.64 1865.66(1.00-5.08) (79.70) (25.04) (2.53) (30.39) (28.99) (33.32) Ratio of 90%Intra-subject Geometric Means Confidence CV (T:R) Interval (%) Test 4AUC_(0→T) 97.75 91.08-104.91 14.37 AUC_(0→∞) 98.87 92.44-105.74 12.09C_(max) 83.90 70.26-100.19 37.05 Test 5 AUC_(0→T) 85.75 79.89-92.0314.37 AUC_(0→∞) 90.58 84.61-96.98 12.09 C_(max) 66.94 56.06-79.94 37.05Test 6 AUC_(0→T) 100.59 93.62-108.07 14.37 AUC_(0→∞) 102.02 95.65-108.8212.09 C_(max) 89.79 74.99-107.51 37.05 Reference: TECFIDERA ® (BiogenIdec), 240 mg dimethyl fumarate, enterically coated pellets Test 4: BLS214 mg fumarate ester, soybean oil, EnteriCare ® DR Soft Capsules; seeTable 62 Test 5: BLS 200 mg fumarate ester, soybean oil, EnteriCare ® DRSoft Capsules; see Table 63 Test 6: BLS 214 mg fumarate ester, soybeanoil, 195 Bloom DR Soft Capsules; see Table 64 *Arithmetic mean (% CV)only ^(†)Median and range only

Example 34

Six formulations of soft capsules comprising particles of a fumarateester having particle size distributions of PSD: d90≤100 μm weremanufactured. The dosage forms comprised six doses of fumarate ester,all with the same fill composition and the same soft gelatin shell. Thedoses were either 90 mg, 95 mg, 100 mg, 115 mg, 200 mg, or 220 mgfumarate ester and comprised 34% fumarate ester, 48% of a mixture ofmono- and di-glycerides (e.g., Capmul® MCM), 3% polyvinylpyrrolidone,10% polyoxyl 40 hydrogenated castor oil, and 5% lactic acid. Tables71-72. The matrix fill was encapsulated in soft gelatin capsulescomprising 195 Bloom gelatin using rotary die encapsulation. See Table66. The 90 mg, 95 mg, 100 mg, and 115 mg dosage forms were 5 ovalcapsules and the 200 mg and 220 mg dosage forms were 12 oval capsules.After manufacturing and drying, the capsules were coated with ahydroxypropylmethylcellulose undercoat and dried. The capsules were thencoated with an enteric coating containing methacrylic acid, ethylacrylate copolymer (e.g., EUDRAGIT® L100-55, Evonik; Acryl-EZE®,Colorcon). Table 67. A polyvinyl alcohol moisture barrier top-coatingwas applied to the enterically coated capsules (e.g., Opadry® amb II,Clear, Colorcon). Table 68.

TABLE 71 Test Formulations 90 mg Dose 95 mg Dose 100 mg Dose Componentmg Weight % mg Weight % mg Weight % Fumarate Ester 90  34.2% 95  34.2%100  34.2% Capmul MCM 125.7  47.8% 132.5  47.8% 139.5  47.8% PovidoneK30 7.9  3.0% 8.3  3.0% 8.8  3.0% Polyoxyl 40 26.3  10.0% 27.7  10.0%29.2  10.0% Hydrogenated Castor Oil Lactic Acid 13.1  5.0% 13.9  5.0%14.6  5.0% TOTAL 263 100.0% 277.4 100.0% 292.1 100.0% Vehicle 173   66%182.4   66% 192.1   66% Lipid 159.9   61% 168.5   61% 177.5   61% API 90  34% 95   34% 100   34% Ratio API:Lipid 1.78 1.78 1.77 1.77 1.78 1.78Ratio API:Vehicle 1.92 1.92 1.92 1.92 1.92 1.92 mmol Fumarate Ester0.62-0.69 0.66-0.73 0.69-0.77

TABLE 72 Test Formulations 115 mg Dose 200 mg Dose 220 mg Dose Componentmg Weight % mg Weight % mg Weight % Fumarate Ester 115  34.2% 200  34.2%220  34.2% Capmul MCM 160.7  47.8% 278.9  47.8% 307.5  47.8% PovidoneK30 10  3.0% 17.5  3.0% 19.1  3.0% Polyoxyl 40 33.5  10.0% 58.4  10.0%64.5  10.0% Hydrogenated Castor Oil Lactic Acid 16.8  5.0% 29.2  5.0%32.1  5.0% TOTAL 336 100.0% 584 100.0% 643.2 100.0% Vehicle 221   66%384   66% 423.2   66% Lipid 204.2   61% 354.8   61% 391.1   61% API 115  34% 200   34% 220   34% Ratio API:Lipid 1.78 1.78 1.77 1.77 1.78 1.78Ratio API:Vehicle 1.92 1.92 1.92 1.92 1.92 1.92 mmol Fumarate Ester0.80-0.88 1.39-1.54 1.53-1.69

1-90. (canceled)
 91. A method for treating or reducing symptoms ofmultiple sclerosis or psoriasis in a subject, the method comprisingadministering: (a) an oral pharmaceutical composition comprising one ormore fumarate esters in an immediate releasing single phase non-aqueousliquid vehicle; and (b) one or more non-steroidal anti-inflammatorydrugs (NSAIDs).
 92. The method of claim 91, wherein the fumarate estercomprises monomethyl fumarate, dimethyl fumarate, a pro-drug thereof, ora combination thereof.
 93. The method of claim 91, wherein the fumarateester comprises monomethyl fumarate.
 94. The method of claim 91, whereinthe fumarate ester comprises dimethyl fumarate.
 95. The method of claim91, wherein the NSAID comprises one or more of aspirin, ibuprofen,naproxene, diclofenac, ketoprofen, celecoxib, or a combination thereof.96. The method of claim 91, wherein the subject is administered the oneor more NSAIDs about 30 minutes before the subject is administered theone or more fumarate esters to reduce the occurrence and severity offlushing side effects in the subject.
 97. The method of claim 91,wherein the one or more NSAIDs is administered in an amount of about 50mg to about 500 mg.
 98. The method of claim 91, wherein the one or moreNSAIDs comprises aspirin administered in an amount of about 325 mg. 99.A method for treating or reducing symptoms of multiple sclerosis orpsoriasis in a subject, the method comprising administering: (a) an oralpharmaceutical composition comprising one or more fumarate esters in animmediate releasing single phase non-aqueous liquid vehicle; and (b) oneor more leukotriene receptor antagonists.
 100. The method of claim 99,wherein the fumarate ester comprises monomethyl fumarate, dimethylfumarate, a pro-drug thereof, or a combination thereof.
 101. The methodof claim 99, wherein the fumarate ester comprises monomethyl fumarate.102. The method of claim 99, wherein the fumarate ester comprisesdimethyl fumarate.
 103. The method of claim 99, wherein the leukotrienereceptor antagonist comprises montelukast or zafirlukast.
 104. Themethod of claim 103, further comprising administering one or moreNSAIDS.
 105. The method of claim 99, wherein the one or more leukotrienereceptor antagonists is administered in an amount of about 10 mg to 20mg.
 106. A method for activating a nuclear factor erythroid-derived2-like (Nrf2) cellular signaling transcriptional pathway in a subject,the method comprising administering a therapeutically effective amountof an oral pharmaceutical composition comprising one or more fumarateesters comprising monomethyl fumarate, dimethyl fumarate, a pro-drugthereof, or a combination thereof in a single phase non-aqueous liquidvehicle.
 107. The method of claim 106, wherein the administration isused to treat or reduce symptoms in a subject with multiple sclerosis orpsoriasis.
 108. The method of claim 106, wherein the administration isused to treat or reduce symptoms in a subject with multiple sclerosis.109. The method of claim 106, wherein the administration is used totreat or reduce symptoms in a subject with psoriasis.